Category Archives: FAK

Akt, Anti-cancer, anti-inflammatory, anti-inflammatory and anti-oxidant, Anti-metastatic, anti-metastatic effect, anti-oxidant, anti-proliferative, c-Myc, cell-cycle arrest, Chapter 7 Isolates and Cancer Research, chemo-preventive, chemo-preventive activity, Colon Cancer or Colorectal cancer, ERK, ERK1, FAK, Fibrosarcoma, HCT-116, metastasis, PI3K, PI3K/Akt, Pinus genus, Rectal cancer, Sarcoma

Pinosylvin

Cancer: Colorectal, lung

Action: Anti-cancer, anti-inflammatory and anti-oxidant, chemo-preventive, anti-metastatic effect

Pinosylvin is a naturally occurring chemo-preventive trans-stilbenoid mainly found in plants of the Pinus genus (Pinus (L.) and Gnetum cleistostachyum (C. Y. Cheng)).

Anti-cancer, Anti-inflammatory and Anti-oxidant

Stilbenes are small molecular weight (approximately 200-300 g/mol), naturally occurring compounds and are found in a wide range of plant sources, aromatherapy products, and dietary supplements. These molecules are synthesized via the phenylpropanoid pathway and share some structural similarities to estrogen. Upon environmental threat, the plant host activates the phenylpropanoid pathway and stilbene structures are produced and subsequently secreted. Stilbenes act as natural protective agents to defend the plant against viral and microbial attack, excessive ultraviolet exposure, and disease. Stilbene compounds, piceatannol, pinosylvin, rhapontigenin, and pterostilbene possess potent anti-cancer, anti-inflammatory and anti-oxidant activities (Roupe et al., 2006).

Colorectal

Pinosylvin, a naturally occurring trans-stilbenoid mainly found in Pinus species, has exhibited a potential cancer chemo-preventive activity. The anti-proliferative activity of pinosylvin was investigated in human colorectal HCT 116 cancer cells.

Pinosylvin was also found to attenuate the activation of proteins involved in focal adhesion kinase (FAK)/c-Src/extracellular signal-regulated kinase (ERK) signaling, and phosphoinositide 3-kinase (PI3K)/Akt/ glycogen synthase kinase 3β (GSK-3β) signaling pathway. Subsequently, pinosylvin suppressed the nuclear translocation of β-catenin, one of downstream molecules of PI3K/Akt/GSK-3β signaling, and these events led to the sequential down-regulation of β-catenin-mediated transcription of target genes including BMP4, ID2, survivin, cyclin D1, MMP7, and c-Myc. These findings demonstrate that the anti-proliferative activity of pinosylvin might be associated with the cell-cycle arrest and down-regulation of cell proliferation regulating signaling pathways in human colorectal cancer cells (Park et al., 2013).

Anti-metastatic

Pinosylvin, a naturally occurring trans-stilbenoid mainly found in Pinus species, exhibits a potential cancer chemo-preventive activity and also inhibits the growth of various human cancer cell lines via the regulation of cell-cycle progression. Pinosylvin suppressed the expression of matrix metalloproteinase (MMP)-2, MMP-9 and membrane type 1-MMP in cultured human fibrosarcoma HT1080 cells. Park et al. (2012) found that pinosylvin inhibited the migration of HT1080 cells in colony dispersion and wound healing assay systems.

The analysis of tumor in lung tissues indicated that the anti-metastatic effect of pinosylvin coincided with the down-regulation of MMP-9 and cyclooxygenase-2 expression, and phosphorylation of ERK1/2 and Akt. These data suggest that pinosylvin might be an effective inhibitor of tumor cell metastasis via modulation of MMPs.

References

Park EJ, Park HJ, Chung HJ, et al. (2012). Anti-metastatic activity of pinosylvin, a natural stilbenoid, is associated with the suppression of matrix metalloproteinases. J Nutr Biochem, 23(8):946-52. doi: 10.1016/j.jnutbio.2011.04.021.


Park EJ, Chung HJ, Park HJ, et al. (2013). Suppression of Src/ERK and GSK-3/ β-catenin signaling by pinosylvin inhibits the growth of human colorectal cancer cells. Food Chem Toxicol, 55:424-33. doi:10.1016/j.fct.2013.01.007.


Roupe KA, Remsberg CM, Yá–ez JA, Davies NM. (2006). Pharmacometrics of stilbenes: seguing towards the clinic. Curr Clin Pharmacol, 1(1):81-101.

Akt, Akt/mTOR/P70S6K, AMPK, angiogenesis, Anti-angiogenic, anti-apoptotic, Anti-cancer, Anti-cancer effect, anti-inflammatory, Anti-metastatic, apoptosis, Apoptotic, BAX, Bladder cancer, CD31, Chapter 7 Isolates and Cancer Research, Colon Cancer or Colorectal cancer, ERK, ERK1, FAK, G0/G1, G1, Glioblastoma, HCT-116, HER-2, HIF, IL-6, induces apoptosis, inhibits angiogenesis, JAK1, JAK2, Lung cancer, Magnolia officinalis, metastasis, MMP2, MTOR, Ovarian cancer, p21, p21/Cip1, p38, p53, P70S6K, PC3, PI3K, PI3K/Akt, PI3K/Akt/MTOR, Pro-apoptotic, Prostate cancer, STAT3, VEGF, VEGF

Magnolol

Cancer:
Bladder, breast, colon, prostate, glioblastoma, ovarian, leukemia, lung

Action: Anti-inflammatory, apoptosis, inhibits angiogenesis, anti-metastatic

Magnolol (Mag), an active constituent isolated from the Chinese herb hou po (Magnolia officinalis (Rehder & Wilson)) has long been used to suppress inflammatory processes. It has anti-cancer activity in colon, hepatoma, and leukemia cell lines.

Anti-inflammatory

Magnolol (Mag) suppressed IL-6-induced promoter activity of cyclin D1 and monocyte chemotactic protein (MCP)-1 for which STAT3 activation plays a role. Pre-treatment of ECs with Mag dose-dependently inhibited IL-6-induced Tyr705 and Ser727 phosphorylation in STAT3 without affecting the phosphorylation of JAK1, JAK2, and ERK1/2. Mag pre-treatment of these ECs dose-dependently suppressed IL-6-induced promoter activity of intracellular cell adhesion molecule (ICAM)-1 that contains functional IL-6 response elements (IREs).

In conclusion, our results indicate that Mag inhibits IL-6-induced STAT3 activation and subsequently results in the suppression of downstream target gene expression in ECs. These results provide a therapeutic basis for the development of Mag as an anti-inflammatory agent for vascular disorders including atherosclerosis (Chen et al., 2006).

Bladder Cancer; Inhibits Angiogenesis

In the present study, Chen et al. (2013) demonstrated that magnolol significantly inhibited angiogenesis in vitro and in vivo, evidenced by the attenuation of hypoxia and vascular endothelial growth factor (VEGF)-induced tube formation of human umbilical vascular endothelial cells, vasculature generation in chicken chorioallantoic membrane, and Matrigel plug.

In hypoxic human bladder cancer cells (T24), treatment with magnolol inhibited hypoxia-stimulated H2O2 formation, HIF-1α induction including mRNA, protein expression, and transcriptional activity as well as VEGF secretion. Interestingly, magnolol also acts as a VEGFR2 antagonist, and subsequently attenuates the downstream AKT/mTOR/p70S6K/4E-BP-1 kinase activation both in hypoxic T24 cells and tumor tissues. As expected, administration of magnolol greatly attenuated tumor growth, angiogenesis and the protein expression of HIF-1α, VEGF, CD31, a marker of endothelial cells, and carbonic anhydrase IX, an endogenous marker for hypoxia, in the T24 xenograft mouse model.

Collectively, these findings strongly indicate that the anti-angiogenic activity of magnolol is, at least in part, mediated by suppressing HIF-1α/VEGF-dependent pathways, and suggest that magnolol may be a potential drug for human bladder cancer therapy.

Colon Cancer; Induces Apoptosis

Emerging evidence has suggested that activation of AMP-activated protein kinase (AMPK), a potential cancer therapeutic target, is involved in apoptosis in colon cancer cells. However, the effects of magnolol on human colon cancer through activation of AMPK remain unexplored.

Magnolol displayed several apoptotic features, including propidium iodide labeling, DNA fragmentation, and caspase-3 and poly(ADP-ribose) polymerase cleavages. Park et al. (2012) showed that magnolol induced the phosphorylation of AMPK in dose- and time-dependent manners.

Magnolol down-regulated expression of the anti-apoptotic protein Bcl2, up-regulated expression of pro-apoptotic protein p53 and Bax, and caused the release of mitochondrial cytochrome c. Magnolol-induced p53 and Bcl2 expression was abolished in the presence of compound C. Magnolol inhibited migration and invasion of HCT-116 cells through AMPK activation. These findings demonstrate that AMPK mediates the anti-cancer effects of magnolol through apoptosis in HCT-116 cells.

Ovarian Cancer

Treatment of HER-2 overexpressing ovarian cancer cells with magnolol down-regulated the HER-2 downstream PI3K/Akt signaling pathway, and suppressed the expression of downstream target genes, vascular endothelial growth factor (VEGF), matrix metalloproteinase 2 (MMP2) and cyclin D1. Consistently, magnolol-mediated inhibition of MMP2 activity could be prevented by co-treatment with epidermal growth factor. Migration assays revealed that magnolol treatment markedly reduced the motility of HER-2 overexpressing ovarian cancer cells. These findings suggest that magnolol may act against HER-2 and its downstream PI3K/Akt/mTOR-signaling network, thus resulting in suppression of HER-2mediated transformation and metastatic potential in HER-2 overexpressing ovarian cancers. These results provide a novel mechanism to explain the anti-cancer effect of magnolol (Chuang et al., 2011).

Lung Cancer

Magnolol has been found to inhibit cell growth, increase lactate dehydrogenase release, and modulate cell cycle in human lung carcinoma A549 cells. Magnolol induced the activation of caspase-3 and cleavage of Poly-(ADP)-ribose polymerase, and decreased the expression level of nuclear factor-κB/Rel A in the nucleus. In addition, magnolol inhibited basic fibroblast growth factor-induced proliferation and capillary tube formation of human umbilical vein endothelial cells. These data indicate that magnolol is a potential candidate for the treatment of human lung carcinoma (Seo et al., 2011).

Prostate Cancer; Anti-metastatic

Matrix metalloproteinases (MMPs) are enzymes involved in various steps of metastasis development. The objective of this study was to study the effects of magnolol on cancer invasion and metastasis using PC-3 human prostate carcinoma cells. Magnolol inhibited cell growth in a dose-dependent manner. In an invasion assay conducted in Transwell chambers, magnolol showed 33 and 98% inhibition of cancer cell at 10 microM and 20 microM concentrations, respectively, compared to the control. The protein and mRNA levels of both MMP-2 and MMP-9 were down-regulated by magnolol treatment in a dose-dependent manner.

These results demonstrate the anti-metastatic properties of magnolol in inhibiting the adhesion, invasion, and migration of PC-3 human prostate cancer cells (Hwang et al., 2010).

Glioblastoma Cancer

Magnolol has been found to concentration-dependently (0-40 microM) decrease the cell number in a cultured human glioblastoma cancer cell line (U373) and arrest the cells at the G0/G1 phase of the cell-cycle.

Pre-treatment of U373 with p21/Cip1 specific antisense oligodeoxynucleotide prevented the magnolol-induced increase of p21/Cip1 protein levels and the decrease of DNA synthesis. Magnolol at a concentration of 100 microM induced DNA fragmentation in U373. These findings suggest the potential applications of magnolol in the treatment of human brain cancers (Chen et al. 2011).

Inhibits Angiogenesis

Magnolol inhibited VEGF-induced Ras activation and subsequently suppressed extracellular signal-regulated kinase (ERK), phosphatidylinositol-3-kinase (PI3K)/Akt and p38, but not Src and focal adhesion kinase (FAK). Interestingly, the knockdown of Ras by short interfering RNA produced inhibitory effects that were similar to the effects of magnolol on VEGF-induced angiogenic signaling events, such as ERK and Akt/eNOS activation, and resulted in the inhibition of proliferation, migration, and vessel sprouting in HUVECs.

In combination, these results demonstrate that magnolol is an inhibitor of angiogenesis and suggest that this compound could be a potential candidate in the treatment of angiogenesis-related diseases (Kim et al., 2013).

References

Chen LC, Liu YC, Liang YC, Ho YS, Lee WS. (2009). Magnolol inhibits human glioblastoma cell proliferation through up-regulation of p21/Cip1. J Agric Food Chem, 57(16):7331-7. doi: 10.1021/jf901477g.


Chen MC, Lee CF, Huang WH, Chou TC. (2013). Magnolol suppresses hypoxia-induced angiogenesis via inhibition of HIF-1 α /VEGF signaling pathway in human bladder cancer cells. Biochem Pharmacol, 85(9):1278-87. doi: 10.1016/j.bcp.2013.02.009.


Chen SC, Chang YL, Wang DL, Cheng JJ. (2006). Herbal remedy magnolol suppresses IL-6-induced STAT3 activation and gene expression in endothelial cells. Br J Pharmacol, 148(2): 226–232. doi: 10.1038/sj.bjp.0706647


Chuang TC, Hsu SC, Cheng YT, et al. (2011). Magnolol down-regulates HER2 gene expression, leading to inhibition of HER2-mediated metastatic potential in ovarian cancer cells. Cancer Lett, 311(1):11-9. doi: 10.1016/j.canlet.2011.06.007.


Hwang ES, Park KK. (2010). Magnolol suppresses metastasis via inhibition of invasion, migration, and matrix metalloproteinase-2/-9 activities in PC-3 human prostate carcinoma cells. Biosci Biotechnol Biochem, 74(5):961-7.


Kim KM, Kim NS, Kim J, et al. (2013). Magnolol Suppresses Vascular Endothelial Growth Factor-Induced Angiogenesis by Inhibiting Ras-Dependent Mitogen-Activated Protein Kinase and Phosphatidylinositol 3-Kinase/Akt Signaling Pathways. Nutr Cancer.


Park JB, Lee MS, Cha EY, et al. (2012). Magnolol-induced apoptosis in HCT-116 colon cancer cells is associated with the AMP-activated protein kinase signaling pathway. Biol Pharm Bull, 35(9):1614-20.


Seo JU, Kim MH, Kim HM, Jeong HJ. (2011). Anti-cancer potential of magnolol for lung cancer treatment. Arch Pharm Res, 34(4):625-33. doi: 10.1007/s12272-011-0413-8.

apoptosis, Apoptotic, barley, BAX, Bcl-2, Breast cancer, Chapter 7 Isolates and Cancer Research, chemo-preventive, Chemo-preventive agent, Chemotherapy, Colon Cancer or Colorectal cancer, ERK, FAK, G1, G2/M, growth-inhibitory, Hordeum vulgare, IKK, including Glycine max, induces apoptosis, KM12L4, MDA-MB-23, MDR, metastasis, p21, p27, p65, Pro-apoptotic, S, Skin cancer, soy, wheat

Lunasin

Cancer: Colon, breast, liver metastasis

Action: Induces apoptosis, MDR

Lunasin is a peptide found in soy, barley, wheat, and rye, including Glycine max [(L.) Merr.], Hordeum vulgare L., Triticum (L.) genus and Secale cereale L.

Colon Cancer; Metastasis

Lunasin bound with α(5)β(1) integrin and internalized into the nucleus of KM12L4 human colon cancer cells. Lunasin (10µM) inhibited the activation of focal adhesion kinase (FAK) by 28%, 39% and 60% in RKO, HCT-116 and KM12L4 human colon cancer cells, respectively. Lunasin caused an increase in the expression of the inhibitor of kappa B alpha (IκB-α), a decrease in nuclear p50 NF-κB and a reduction in the migration of cancer cells. Lunasin (4mg/kg bw) inhibited metastasis and potentiated the effect of oxaliplatin by reducing the expression of proliferating cell nuclear antigen.

Liver metastatic nodules were reduced from 28 (PBS) to 14 (lunasin, P=0.047) while combination of lunasin and oxaliplatin to 5 (P=0.004). The tumor burden was reduced from 0.13 (PBS) to 0.10 (lunasin, P=0.039) to 0.04 (lunasin+oxaliplatin, P<0.0001). Moreover, lunasin potentiated the effect of oxaliplatin in modifying expression of proteins involved in apoptosis and metastasis including Bax, Bcl-2, IKK-α and p-p65. Lunasin inhibited metastasis of human colon cancer cells by direct binding with α(5)β(1) integrin suppressing FAK/ERK/NF-κB signaling, and potentiated the effect of oxaliplatin in preventing the outgrowth of metastasis (Dia et al., 2011).

Induces Apoptosis

Galvez et al. (2001) demonstrated previously that transfection of mammalian cells with the lunasin gene arrests mitosis, leading to cell death. Here they show that exogenous application of the lunasin peptide inhibits chemical carcinogen-induced transformation of murine fibroblast cells to cancerous foci. The results suggest a mechanism whereby lunasin selectively induces apoptosis, mostly in cells undergoing transformation, by preventing histone acetylation. In support of this, lunasin selectively induces apoptosis in E1A-transfected cells but not in nontransformed cells. Finally, in the SENCAR mouse skin cancer model, dermal application of lunasin (250 microg/week) reduces skin tumor incidence by approximately 70%, decreases tumor yield/mouse, and delays the appearance of tumors by 2 weeks relative to the positive control. These results point to the role of lunasin as a new chemo-preventive agent that functions possibly via a chromatin modification mechanism.

Breast Cancer

Combinations of two or more chemo-preventive agents are currently being used to achieve greater inhibitory effects on breast cancer cells. This study reveals that both aspirin and lunasin inhibit, in a dose-dependent manner, human estrogen-independent breast cancer MDA-MB-231 cell proliferation.

These compounds arrest the cell-cycle in the S- and G1-phases, respectively, acting synergistically to induce apoptosis. The cell growth-inhibitory effect of a lunasin/aspirin combination is achieved, at least partially, by modulating the expression of genes encoding G1 and S-phase regulatory proteins. Lunasin/aspirin therapy exerts its potent pro-apoptotic effect, at least partially achieved through modulating the extrinsic-apoptosis dependent pathway.

Therefore, our results suggest that a combination of these two compounds is a promising strategy to prevent/treat breast cancer (Hsieh et al., 2010).

Colon Cancer; MDR

Various human colon cancer cell lines which underwent metastasis were evaluated in vitro using cell flow cytometry and fluorescence microscopy. Lunasin cytotoxicity to different colon cancer cells correlated with the expression of α5b1 integrin was investigated, being most potent to KM12L4 cells (IC50 = 13 µM). Lunasin arrested cell-cycle at G2/M phase with concomitant increase in the expression of cyclin-dependent kinase inhibitors p21 and p27. Lunasin (5–25 µM) activated the apoptotic mitochondrial pathway as evidenced by changes in the expressions of Bcl-2, Bax, nuclear clusterin, cytochrome c and caspase-3 in KM12L4 and KM12L4-OxR.

Lunasin increased the activity of initiator caspase-9 leading to the activation of caspase-3 and also modified the expression of human extracellular matrix and adhesion genes, down-regulating integrin α5, SELE, MMP10, integrin β2 and COL6A1 by 5.01-, 6.53-, 7.71-, 8.19- and 10.10-fold, respectively, while up-regulating COL12A1 by 11.61-fold. Lunasin can be used in cases where resistance to chemotherapy developed (Dia et al., 2011).

References

Dia VP, Gonzalez de Mejia E. (2011). Lunasin potentiates the effect of oxaliplatin preventing outgrowth of colon cancer metastasis, binds to α5β1 integrin and suppresses FAK/ERK/NF-κ B signaling, Cancer Lett, 313(2):167-80.


Dia VP, Gonzalez de Mejia E. (2011). Lunasin induces apoptosis and modifies the expression of genes associated with extracellular matrix and cell adhesion in human metastatic colon cancer cells. Mol Nutr Food Res, 55(4):623-34. doi: 10.1002/mnfr.201000419.


Galvez AF, Chen N, Macasieb J, de Lumen BO. (2001). Chemo-preventive property of a soybean peptide (lunasin) that binds to deacetylated histones and inhibits acetylation. Cancer Res, 61(20):7473-8.


Hsieh CC, Hern‡ndez-Ledesma B, de Lumen BO. (2010). Lunasin, a novel seed peptide, sensitizes human breast cancer MDA-MB-231 cells to aspirin-arrested cell-cycle and induced apoptosis. Chem Biol Interact, 186(2):127-34. doi: 10.1016/j.cbi.2010.04.027.

AhR, Akt, angiogenesis, Anti-cancer, anti-proliferative, anti-proliferative effect, anti-tumor, anti-tumor activity, apoptosis, Apoptotic, BCR, Breast cancer, CDK, CDK2, cell-cycle arrest, Chapter 7 Isolates and Cancer Research, CYP1A1, CYP1B1, FAK, G1, G2/M, Head and neck cancer, inflammation, inhibits angiogenesis, Isatis (L.) genus, Lung cancer, MCF-7, metastasis, Prostate cancer, RS4;11 and MV4;1, STAT3

Indirubin

Cancer:
Chronic myelogenous leukemia, lung, breast, head and neck, prostate, acute myeloid leukemia, prostate

Action: Aryl hydrocarbon Receptor (AhR) regulator, inhibits angiogenesis

Indirubin is the active component of many plants from the Isatis (L.) genus, including Isatis tinctoria (L.).

Indirubin is the active ingredient of Danggui Longhui Wan, a mixture of plants that is used in traditional Chinese medicine to treat chronic diseases. Indirubin and its analogues are potent inhibitors of cyclin-dependent kinases (CDKs). The crystal structure of CDK2 in complex with indirubin derivatives shows that indirubin interacts with the kinase's ATP-binding site through van der Waals interactions and three hydrogen bonds. Indirubin-3'-monoxime inhibits the proliferation of a large range of cells, mainly through arresting the cells in the G2/M phase of the cell-cycle. These results have implications for therapeutic optimization of indigoids (Hoessel et al., 1999).

Formula; Huang Lian (Rhizoma Coptidis Recens), Huang Qin (Radix Scutellariae Baicalensis), Huang Bai (Cortex Phellodendri), Zhi Zi (Fructus Gardeniae Jasminoidis), Dang Gui (Radix Angelicae Sinensis), Lu Hui (Herba Aloes), Long Dan Cao (Radix Gentianae Longdancao), Da Huang (Radix et Rhizoma Rhei), Mu Xiang (Radix Aucklandiae Lappae), Qing Dai (Indigo Pulverata Levis), She Xiang (Secretio Moschus)

Leukemia

Indirubin, a 3, 2' bisindole isomer of indigo was originally identified as the active principle of a traditional Chinese preparation and has been proven to exhibit anti-leukemic effectiveness in chronic myelocytic leukemia. Indirubin was detected to represent a novel lead structure with potent inhibitory potential towards cyclin-dependent kinases (CDKs) resulting from high affinity binding into the enzymes ATP binding site. This seminal finding triggered research to improve the pharmacological activities of the parent molecule within comprehensive structure-activity studies. Molecular modifications made novel anti-cancer compounds accessible with strongly improved CDK inhibitory potential and with broad-spectrum anti-tumor activity.

This novel family of compounds holds strong promise for clinical anti-cancer activity and might be useful also in several important non-cancer indications, including Alzheimer's disease or diabetes (Eisenbrand et al., 2004).

Aryl Hydrocarbon Receptor (AhR) Regulator; Breast Cancer

The aryl hydrocarbon receptor (AhR), when activated by exogenous ligands such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), regulates expression of several phase I and phase II enzymes and is also involved in the regulation of cell proliferation. One putative endogenous ligand is indirubin, which was recently identified in human urine and bovine serum. We determined the effect of indirubin in MCF-7 breast cancer cells on induction of the activities of cytochromes P450 (CYP) 1A1 and 1B1. With 4 hours exposure, the effects of indirubin and TCDD at 10nM on CYP activity were comparable, but the effects of indirubin, unlike those of TCDD, were transitory. Indirubin-induced ethoxyresorufin-O-deethylase activity was maximal by 6–9 hours post-exposure and had disappeared by 24 hours, whereas TCDD-induced activities remained elevated for at least 72 hours.

Thus, if indirubin is an endogenous AhR ligand, then AhR-mediated signaling by indirubin is likely to be transient and tightly controlled by the ability of indirubin to induce CYP1A1 and CYP1B1, and hence its own metabolism (Spink et al., 2003).

Chronic Myelogenous Leukemia (CML)

Indirubin is the major active anti-tumor component of a traditional Chinese herbal medicine used for treatment of chronic myelogenous leukemia (CML). In a study investigating its mechanism of action, indirubin derivatives (IRDs) were found to potently inhibit Signal Transducer and Activator of Transcription 5 (Stat5) protein in CML cells.

Compound E804, which is the most potent in this series of IRDs, blocked Stat5 signaling in human K562 CML cells, imatinib-resistant human KCL-22 CML cells expressing the T315I mutant Bcr-Abl (KCL-22M), and CD34-positive primary CML cells from patients.

In sum, these findings identify IRDs as potent inhibitors of the SFK/Stat5 signaling pathway downstream of Bcr-Abl, leading to apoptosis of K562, KCL-22M and primary CML cells. IRDs represent a promising structural class for development of new therapeutics for wild type or T315I mutant Bcr-Abl-positive CML patients (Nam et al., 2012).

Lung Cancer

A novel indirubin derivative, 5'-nitro-indirubinoxime (5'-NIO), exhibits a strong anti-cancer activity against human cancer cells. Here, the 5'-NIO-mediated G1 cell-cycle arrest in lung cancer cells was associated with a decrease in protein levels of polo-like kinase 1 (Plk1) and peptidyl-prolyl cis/trans isomerase Pin1. These findings suggest that 5'-NIO have potential anti-cancer efficacy through the inhibition of Plk1 or/and Pin1 expression (Yoon et al., 2012).

The control lung tissue showed a normal architecture with clear alveolar spaces. Interestingly, the indirubin-3-monoxime treated groups showed reduced adenocarcinoma with appearance of alveolar spaces. Transmission Electron Microscopic (TEM) studies of lung sections of [B(α)P]-induced lung cancer mice showed the presence of phaemorphic cells with dense granules and increased mitochondria.

The lung sections of mice treated with indirubin-3-monoxime showed the presence of shrunken, fragmented, and condensed nuclei implying apoptosis. The effects were dose-dependent and prominent in 10 mg/kg/5 d/week groups, suggesting the therapeutic role of indirubin analogue against this deadly human malignancy. These results indicate that indirubin-3-monoxime brings anti-tumor effect against [B(α)P]-induced lung cancer by its apoptotic action in A/J mice (Ravichandran et al., 2010).

Head and Neck Cancer

The effects of 5'-nitro-indirubinoxime (5'-NIO), an indirubin derivative, on metastasis of head and neck cancer cells were investigated and the underlying molecular mechanisms involved in this process explored.

After treatment of head and neck cancer cells with 5'-NIO, cell metastatic behaviors such as colony formation, invasion, and migration were inhibited in a concentration-dependent manner. 5'-NIO inhibited the beta1 Integrin/FAK/Akt pathway which can then facilitate invasion and/or migration of cancer cells through the extracellular matrix (ECM). Moreover, treatment of head and neck cancer cell with Integrin β1 siRNA or FAK inhibitor effectively inhibited the invasion and migration, suggesting their regulatory role in invasiveness and migration of head and neck cancer cells. It was concluded that 5'-NIO inhibits the metastatic ability of head and neck cancer cells by blocking the Integrin β1/FAK/Akt pathway (Kim et al., 2011).

Prostate Cancer; Inhibits Angiogenesis

Indirubin, the active component of a traditional Chinese herbal medicine, Banlangen, has been shown to exhibit anti-tumor and anti-inflammation effects; however, its role in tumor angiogenesis, the key step involved in tumor growth and metastasis, and the involved molecular mechanism is unknown.

To address this shortfall in the existing research, it was identified that indirubin inhibited prostate tumor growth through inhibiting tumor angiogenesis. It was found that indirubin inhibited angiogenesis in vivo. The inhibition activity of indirubin in endothelial cell migration, tube formation and cell survival in vitro has also been shown. Furthermore, indirubin suppressed vascular endothelial growth factor receptor 2-mediated Janus kinase (JAK)/STAT3 signaling pathway. This study provided the first evidence for anti-tumor angiogenesis activity of indirubin and the related molecular mechanism.

These investigations suggest that indirubin is a potential drug candidate for angiogenesis-related diseases (Zhang et al., 2011).

Acute Myeloid Leukemia

Indirubin derivatives were identified as potent FLT3 tyrosine kinase inhibitors with anti-proliferative activity at acute myeloid leukemic cell lines, RS4;11 and MV4;11 which express FLT3-WT and FLT3-ITD mutation, respectively. Among several 5 and 5'-substituted indirubin derivatives, 5-fluoro analog, 13 exhibited potent inhibitory activity at FLT3 (IC(50)=15 nM) with more than 100-fold selectivity versus 6 other kinases and potent anti-proliferative effect for MV4;11 cells (IC(50)=72 nM) with 30-fold selectivity versus RS4;11 cells.

Cell cycle analysis indicated that compound 13 induced cell-cycle arrest at G(0)/G(1) phase in MV4;11 cells (Choi et al., 2010).

References

Choi SJ, Moon MJ, Lee SD, et al. (2010). Indirubin derivatives as potent FLT3 inhibitors with anti-proliferative activity of acute myeloid leukemic cells. Bioorg Med Chem Lett, 20(6):2033-7.


Eisenbrand G, Hippe F, Jakobs S, Muehlbeyer S. (2004). Molecular mechanisms of indirubin and its derivatives: novel anti-cancer molecules with their origin in traditional Chinese phytomedicine. J Cancer Res Clin Oncol, 130(11):627-35


Hoessel R, Leclerc S, Endicott JA, et al. (1999). Indirubin, the active constituent of a Chinese antileukaemia medicine, inhibits cyclin-dependent kinases. Nat Cell Biol, 1(1):60-7.


Kim SA, Kwon SM, Kim JA, et al. (2011). 5'-Nitro-indirubinoxime, an indirubin derivative, suppresses metastatic ability of human head and neck cancer cells through the inhibition of Integrin β 1/FAK/Akt signaling. Cancer Lett, 306(2):197-204.


Nam S, Scuto A, Yang F, et al. (2012). Indirubin derivatives induce apoptosis of chronic myelogenous leukemia cells involving inhibition of Stat5 signaling. Mol Oncol, 6(3):276-83.


Ravichandran K, Pal A, Ravichandran R. (2010). Effect of indirubin-3-monoxime against lung cancer as evaluated by histological and transmission electron microscopic studies. Microsc Res Tech, 73(11):1053-8.


Spink BC, Hussain MM, Katz BH, Eisele L, Spink DC. (2003). Transient induction of cytochromes P450 1A1 and 1B1 in MCF-7 human breast cancer cells by indirubin. Biochem Pharmacol, 66(12):2313-21.


Yoon HE, Kim SA, Choi HS, et al. (2012). Inhibition of Plk1 and Pin1 by 5'-nitro-indirubinoxime suppresses human lung cancer cells. Cancer Lett, 316(1):97-104.


Zhang X, Song Y, Wu Y, et al. (2011). Indirubin inhibits tumor growth by anti-tumor angiogenesis via blocking VEGFR2-mediated JAK/STAT3 signaling in endothelial cell. Int J Cancer, 129(10):2502-11. doi: 10.1002/ijc.25909.

Akt, angiogenesis, Anti-cancer, Breast cancer, Chapter 7 Isolates and Cancer Research, ER, ERK1, FAK, Glycyrrhiza glabra, growth-inhibitory, inhibits angiogenesis, inhibits metastasis, MDA-MB-231, metastasis

Glabridin

Cancer: Breast

Action: Inhibits metastasis, inhibits angiogenesis

Glabridin is a novel phytoestrogen isolated from licorice extract (Glycyrrhiza glabra (L.))

Breast Cancer Growth; Estrogen agonist

Glabridin and its derivatives bind to the human ER and have been found to act as an estrogen agonist in the induction of an estrogen response marker, such as CK activity, in vivo, to induce uterus wet weight, and to stimulate human breast cancer cell growth. There is an increasing demand for natural compounds that improve women's health by mimicking the critical benefits of estrogen to the bones and the cardiovascular system but avoiding its deleterious effects on the breast and uterus.

The estrogenic properties of glabridin, the major isoflavan in licorice root, were tested in view of the resemblance of its structure and lipophilicity to those of estradiol. The results indicate that glabridin is a phytoestrogen, binding to the human estrogen receptor and stimulating creatine kinase activity in rat uterus, epiphyseal cartilage, diaphyseal bone, aorta, and left ventricle of the heart. This indicates that isoflavans have estrogen-like activities. Glabridin and its derivatives exhibited varying degrees of estrogen receptor agonism in different tests and demonstrated growth-inhibitory actions on breast cancer cells (Tamir et al., 2000).

Inhibits Metastasis, Inhibits Angiogenesis

Glabridin exhibited effective inhibition of cell metastasis by decreasing cancer cell migration and invasion of metastatic MDA-MB-231 breast cancer cells. In addition, glabridin also blocked human umbilical vein endothelial cells (HUVEC) migration and decreased MDA-MB-231-mediated angiogenesis. Further investigation revealed that the inhibition of cancer angiogenesis by glabridin was also evident in a nude mice model. Blockade of MDA-MB-231 cells and HUVEC migration was associated with an increase of αγβ3 integrin proteosome degradation. Glabridin also decreased the active forms of FAK and Src, and enhanced levels of inactivated phosphorylated Src (Tyr 416), decreasing the interaction of FAK and Src.

Inhibition of the FAK/Src complex by glabridin also blocked AKT and ERK1/2 activation, resulting in reduced activation of RhoA as well as myosin light chain phosphorylation. This study demonstrates that glabridin may be a novel anti-cancer agent for the treatment of breast cancer in three different ways: inhibition of migration, invasion and angiogenesis (Hsu et al., 2011).

References

Hsu YL, Wu LY, Hou MF, et al. (2011). Glabridin, an isoflavan from licorice root, inhibits migration, invasion and angiogenesis of MDA-MB-231 human breast adenocarcinoma cells by inhibiting focal adhesion kinase/Rho signaling pathway. Molecular Nutrition & Food Research, 55(2):318–27. doi: 10.1002/mnfr.201000148.


Tamir S, Eizenberg M, Somjen D, et al. (2000). Estrogenic and Anti-proliferative Properties of Glabridin from Licorice in Human Breast Cancer Cells. Cancer Res, 60:5704

apoptosis, Causes cell-cycle arrest, cell-cycle arrest, Cervical cancer, Chapter 7 Isolates and Cancer Research, EGFR, FAK, G2/M, Geranium genus, Melanoma, S

Geraniin

Cancer: Melanoma, T cell leukemia, cervical

Action: Causes cell-cycle arrest

Melanoma

Geraniin, a form of tannin separated from Geranium genus (including Geranium niveum (S. Watson)), causes cell death through induction of apoptosis. Geraniin triggered cell death by caspase-3-mediated cleavage of FAK and was associated with the up-regulation of Fas ligand expression, the activation of caspase-8, the cleavage of Bid, and the induction of cytochrome c release from mitochondria to the cytosol in human melanoma cells (Lee et al., 2008).

Leukemia, Cervical Cancer

Different concentrations of geraniin, the level of expression of the client proteins c-Raf, pAkt, and EGFR, was strongly down-regulated. Geraniin was able to inhibit in vitro the Hsp90α ATPase activity in a dose-dependent manner, with an inhibitory efficiency comparable to that measured for 17-AAG. In addition, this compound compromised the chaperone activity of Hsp90α, monitored by the citrate synthase thermal induced aggregation assay. Geraniin decreased the viability of HeLa and Jurkat cell lines and caused an arrest in G2/M phase. These results, along with the finding that geraniin did not exert any appreciable cytotoxicity on normal cells, encourage further studies on this compound as a promising chemical scaffold for the design of new Hsp90 inhibitors (Vassallo et al., 2013).

References

Lee JC, Tsai CY, Kao JY, et al. (2008). Geraniin-mediated apoptosis by cleavage of focal adhesion kinase through up-regulation of Fas ligand expression in human melanoma cells. Mol Nutr Food Res, 52(6):655-63.


Vassallo A, Vaccaro MC, De Tommasi N, Dal Piaz F, Leone A. (2013). Identification of the plant compound geraniin as a novel hsp90 inhibitor. PLoS One, 8(9):e74266. doi: 10.1371/journal.pone.0074266.

A2058, Akt, anti-carcinogenic, anti-inflammatory, Anti-metastatic, anti-mitogenic, anti-oxidant, anti-proliferative, apoptosis, Apoptotic, Breast cancer, Breast cancer cell lines, Cervical cancer, Chapter 7 Isolates and Cancer Research, chemo-preventive, Chemo-preventive agent, Chemotherapy, Cytostatic, cytotoxic, EMT, ER, FAK, honeybee hives, Immune, Immunomodulatory, inflammation, inhibits NF-κB, JNK, Lung cancer, MAPK, MCF-7/Adr, MCF-7/wt, Mcl-1, Melanoma, Oral cancer, p38, p65, PANC-1, Pancreatic cancer, Prostate cancer, ROS, S, SCC-9, TIMP-2, TNF, Twist

Caffeic acid phenethyl ester (CAPE)

Cancer:
Breast, prostate, leukemia, cervical., oral., melanoma

Action: EMT, anti-mitogenic, anti-carcinogenic, anti-inflammatory, immunomodulatory

Anti-mitogenic, Anti-carcinogenic, Anti-inflammatory, Immunomodulatory Properties

Caffeic acid phenethyl ester (CAPE), an active component of propolis from honeybee hives, is known to have anti-mitogenic, anti-carcinogenic, anti-inflammatory, and immunomodulatory properties. A variety of in vitro pharmacology for CAPE has been reported. A study using CAPE showed a positive effect on reducing carcinogenic incidence. It is known to have anti-mitogenic, anti-carcinogenic, anti-inflammatory, and immunomodulatory properties in vitro (Orban et al., 2000) Another study also showed that CAPE suppresses acute immune and inflammatory responses and holds promise for therapeutic uses to reduce inflammation (Huang et al., 1996).

Caffeic acid phenethyl ester (CAPE) specifically inhibits NF-κB at µM concentrations and shows ability to stop 5-lipoxygenase-catalyzed oxygenation of linoleic acid and arachidonic acid. Previous studies have demonstrated that CAPE exhibits anti-oxidant, anti-inflammatory, anti-proliferative, cytostatic, anti-viral., anti-bacterial., anti-fungal., and, most importantly, anti-neoplastic properties (Akyol et al., 2013).

Multiple Immunomodulatory and Anti-inflammatory Activities

The results show that the activation of NF-kappa B by tumor necrosis factor (TNF) is completely blocked by CAPE in a dose- and time-dependent manner. Besides TNF, CAPE also inhibited NF-kappa B activation induced by other inflammatory agents including phorbol ester, ceramide, hydrogen peroxide, and okadaic acid. Since the reducing agents reversed the inhibitory effect of CAPE, it suggests the role of critical sulfhydryl groups in NF-kappa B activation. CAPE prevented the translocation of the p65 subunit of NF-kappa B to the nucleus and had no significant effect on TNF-induced I kappa B alpha degradation, but did delay I kappa B alpha resynthesis. When various synthetic structural analogues of CAPE were examined, it was found that a bicyclic, rotationally constrained, 5,6-dihydroxy form was superactive, whereas 6,7-dihydroxy variant was least active.

Thus, overall our results demonstrate that CAPE is a potent and a specific inhibitor of NF-kappa B activation and this may provide the molecular basis for its multiple immunomodulatory and anti-inflammatory activities (Natarajan et al., 1996).

Breast Cancer

Aqueous extracts from Thymus serpyllum (ExTs), Thymus vulgaris (ExTv), Majorana hortensis (ExMh), and Mentha piperita (ExMp), and the phenolic compounds caffeic acid (CA), rosmarinic acid (RA), lithospermic acid (LA), luteolin-7-O-glucuronide (Lgr), luteolin-7-O-rutinoside (Lr), eriodictiol-7-O-rutinoside (Er), and arbutin (Ab), were tested on two human breast cancer cell lines: Adriamycin-resistant MCF-7/Adr and wild-type MCF-7/wt.

ExMh showed the highest cytotoxicity, especially against MCF-7/Adr, whereas ExMp was the least toxic; particularly against MCF-7/wt cells. RA and LA exhibited the strongest cytotoxicity against both MCF-7 cell lines, over 2-fold greater than CA and Lgr, around 3-fold greater than Er, and around 4- to 7-fold in comparison with Lr and Ab. Except for Lr and Ab, all other phytochemicals were more toxic against MCF-7/wt, and all extracts exhibited higher toxicity against MCF-7/Adr. It might be concluded that the tested phenolics exhibited more beneficial properties when they were applied in the form of extracts comprising their mixtures (Berdowska et al., 2013).

Prostate Cancer

Evidence is growing for the beneficial role of selective estrogen receptor modulators (SERM) in prostate diseases. Caffeic acid phenethyl ester (CAPE) is a promising component of propolis that possesses SERM activity. CAPE-induced inhibition of AKT phosphorylation was more prominent (1.7-folds higher) in cells expressing ER-α such as PC-3 compared to LNCaP. In conclusion, CAPE enhances the anti-proliferative and cytotoxic effects of DOC and PTX in prostate cancer cells (Tolba et al., 2013).

EMT, Prostate Cancer

CAPE suppressed the expression of Twist 2 and growth of PANC-1 xenografts without significant toxicity. CAPE could inhibit the orthotopic growth and EMT of pancreatic cancer PANC-1 cells accompanied by down-regulation of vimentin and Twist 2 expression (Chen et al., 2013).

CAPE is a well-known NF-κB inhibitor. CAPE has been used in folk medicine as a potent anti-inflammatory agent. Recent studies indicate that CAPE treatment suppresses tumor growth and Akt signaling in human prostate cancer cells (Lin et al., 2013). Combined treatments of CAPE with chemotherapeutic drugs exhibit synergistic suppression effects. Pharmacokinetic studies suggest that intraperitoneal injection of CAPE at concentration of 10mg/kg is not toxic. CAPE treatment sensitizes cancer cells to chemotherapy and radiation treatments. In addition, CAPE treatment protects therapy-associated toxicities (Liu et al., 2013).

Cervical Cancer

CAPE preferentially induced S- and G2 /M-phase cell-cycle arrests and initiated apoptosis in human cervical cancer lines. The effect was found to be associated with increased expression of E2F-1, as there is no CAPE-mediated induction of E2F-1 in the pre-cancerous cervical Z172 cells. CAPE also up-regulated the E2F-1 target genes cyclin A, cyclin E and apoptotic protease activating of factor 1 (Apaf-1) but down-regulated cyclin B and induced myeloid leukemia cell differentiation protein (Mcl-1) (Hsu et al., 2013).

Oral Cancer

CAPE attenuated SCC-9 oral cancer cells migration and invasion at noncytotoxic concentrations (0  µM to 40 µM). CAPE exerted its inhibitory effects on MMP-2 expression and activity by upregulating tissue inhibitor of metalloproteinase-2 (TIMP-2) and potently decreased migration by reducing focal adhesion kinase (FAK) phosphorylation and the activation of its downstream signaling molecules p38/MAPK and JNK (Peng et al., 2012).

Melanoma

CAPE is suggested to suppress reactive-oxygen species (ROS)-induced DNA strand breakage in human melanoma A2058 cells when compared to other potential protective agents. CAPE can be applied not only as a chemo-preventive agent but also as an anti-metastatic therapeutic agent in lung cancer and because CAPE is a nuclear factor-κB (NF-κB) inhibitor and 5α reductase inhibitor, it has potential for the treatment of prostate cancer (Ozturk et al., 2012).

References

Akyol S, Ozturk G, Ginis Z, et al. (2013). In vivo and in vitro antõneoplastic actions of caffeic acid phenethyl ester (CAPE): therapeutic perspectives. Nutr Cancer, 65(4):515-26. doi: 10.1080/01635581.2013.776693.


Berdowska I, Ziel iński B, Fecka I, et al. (2013). Cytotoxic impact of phenolics from Lamiaceae species on human breast cancer cells. Food Chem, 15;141(2):1313-21. doi: 10.1016/j.foodchem.2013.03.090.


Chen MJ, Shih SC, Wang HY, et al. (2013). Caffeic Acid phenethyl ester inhibits epithelial-mesenchymal transition of human pancreatic cancer cells. Evid Based Complement Alternat Med, 2013:270906. doi: 10.1155/2013/270906.


Hsu TH, Chu CC, Hung MW, et al. (2013). Caffeic acid phenethyl ester induces E2F-1-mediated growth inhibition and cell-cycle arrest in human cervical cancer cells. FEBS J, 280(11):2581-93. doi: 10.1111/febs.12242.


Huang MT, Ma W, Yen P, et al. (1996). Inhibitory effects of caffeic acid phenethyl ester (CAPE) on 12-O-tetradecanoylphorbol-13-acetate-induced tumor promotion in mouse skin and the synthesis of DNA, RNA and protein in HeLa cells. Carcinogenesis, 17(4):761–5. doi:10.1093/carcin/17.4.761.


Lin HP, Lin CY, Liu CC, et al. (2013). Caffeic Acid phenethyl ester as a potential treatment for advanced prostate cancer targeting akt signaling. Int J Mol Sci, 14(3):5264-83. doi: 10.3390/ijms14035264.


Liu CC, Hsu JM, Kuo LK, et al. (2013). Caffeic acid phenethyl ester as an adjuvant therapy for advanced prostate cancer. Med Hypotheses, 80(5):617-9. doi: 10.1016/j.mehy.2013.02.003.


Natarajan K, Singh S, Burke TR Jr, Grunberger D, Aggarwal BB. (1996). Caffeic acid phenethyl ester is a potent and specific inhibitor of activation of nuclear transcription factor NF-kappa B. Proc Natl Acad Sci USA, 93(17):9090-5.


Orban Z, Mitsiades N, Burke TR, Tsokos M, Chrousos GP. (2000). Caffeic acid phenethyl ester induces leukocyte apoptosis, modulates nuclear factor-kappa B and suppresses acute inflammation. Neuroimmunomodulation, 7(2): 99–105. doi:10.1159/000026427.


Ozturk G, Ginis Z, Akyol S, et al. (2012). The anti-cancer mechanism of caffeic acid phenethyl ester (CAPE): review of melanomas, lung and prostate cancers. Eur Rev Med Pharmacol Sci, 16(15):2064-8.


Peng CY, Yang HW, Chu YH, et al. (2012). Caffeic Acid phenethyl ester inhibits oral cancer cell metastasis by regulating matrix metalloproteinase-2 and the mitogen-activated protein kinase pathway. Evid Based Complement Alternat Med, 2012:732578. doi: 10.1155/2012/732578.


Tolba MF, Esmat A, Al-Abd AM, et al. (2013). Caffeic acid phenethyl ester synergistically enhances docetaxel and paclitaxel cytotoxicity in prostate cancer cells. IUBMB Life, 65(8):716-29. doi: 10.1002/iub.1188.

A375 and Hs294, A431, angiogenesis, anti-apoptotic, Anti-cancer, Anti-cancer effect, anti-inflammatory, Anti-metastatic, anti-oxidant, anti-oxidative, anti-proliferative, anti-proliferative effect, apoptosis, apoptosis induction, Apoptotic, Autophagy, BAX, Bcl-2, Bcl-xL, BCRP/ABCG2, Berberis amurensis, BIU-87 and T24, Breast cancer, Breast cancer cell lines, CDK, cell-cycle arrest, Cervical cancer, Chapter 7 Isolates and Cancer Research, chemo-enhancing, chemo-preventive, Chemo-preventive agent, Chemoprevention, Chemotherapy, Colon Cancer or Colorectal cancer, COX-2, cytotoxic, Diarrhea or Constipation, ER, ER-negative, ER-positive, FAK, G0/G1, G1, growth-inhibitory, hepato-protective, HIF, HL-60, inflammation, Leukemia, Liver cancer, LNCaP, DU145, PC-3, Lymphoma, MCF-7, MCF-7, MDA-MB-231, Melanoma, metastasis, Nitric Oxide, OVCAR-3, SKOV-3, PARP, PC3, PGE2, Pro-apoptotic, Prostate cancer, Radio-sensitizer, radiotherapy, ROS, SiHa and CaSki, Skin cancer, T98G, type, u-PA, VEGF, VEGF

Berberine

Cancer:
Liver,leukemia, breast, prostate, epidermoid (squamous-cell carcinoma), cervical.,testicular, melanoma, lymphoma, hepatoma

Action: Radio-sensitizer, anti-inflammatory, cell-cycle arrest, angiogenesis, chemo-enhancing, anti-metastatic, anti-oxidative

Berberine is a major phytochemical component of the roots and bark of herbal plants such as Berberis, Hydrastis canadensis and Coptis chinensis. It has been implicated in the cytotoxic effects on multiple cancer cell lines.

Anti-inflammatory

Berberine is an isoquinoline alkaloid widely distributed in natural herbs, including Rhizoma Coptidis chinensis and Epimedium sagittatum (Sieb. et Zucc.), a widely prescribed Chinese herb (Chen et al., 2008). It has a broad range of bioactivities, such as anti-inflammatory, anti-bacterial., anti-diabetes, anti-ulcer, sedation, protection of myocardial ischemia-reperfusion injury, expansion of blood vessels, inhibition of platelet aggregation, hepato-protective, and neuroprotective effects (Lau et al., 2001; Yu et al., 2005; Kulkarni & Dhir, 2010; Han et al., 2011; Ji, 2011). Berberine has been used in the treatment of diarrhea, neurasthenia, arrhythmia, diabetes, and so forth (Ji, 2011).

Angiogenesis, Chemo-enhancing

Inhibition of tumor invasion and metastasis is an important aspect of berberine's anti-cancer activities (Tang et al., 2009; Ho et al., 2009). A few studies have reported berberine's inhibition of tumor angiogenesis (Jie et al., 2011; Hamsa & Kuttan, 2012). In addition, its combination with chemotherapeutic drugs or irradiation could enhance the therapeutic effects (Youn et al., 2008; Hur et al., 2009).

Cell-cycle Arrest

The potential molecular targets and mechanisms of berberine are rather complicated. Berberine interacts with DNA or RNA to form a berberine-DNA or a berberine-RNA complex, respectively (Islam & Kumar. 2009; Li et al., 2012). Berberine is also identified as an inhibitor of several enzymes, such as N-acetyltransferase (NAT), cyclooxygenase-2 (COX-2), and telomerase (Sun et al., 2009).

Other mechanisms of berberine are mainly related to its effect on cell-cycle arrest and apoptosis, including regulation of cyclin-dependent kinase (CDK) family of proteins (Sun et al., 2009; Mantena, Sharma, & Katiyar, 2006) and expression regulation of B-cell lymphoma 2 (Bcl-2) family of proteins (such as Bax, Bcl-2, and Bcl-xL) (Sun et al., 2009), and caspases (Eom et al., 2010; Mantena, Sharma, & Katiyar, 2006). Furthermore, berberine inhibits the activation of the nuclear factor κ-light-chain-enhancer of activated B cells (NF-κB) and induces the formation of intracellular reactive oxygen species (ROS) in cancer cells (Sun et al., 2009; Eom et al., 2010). Interestingly, these effects might be specific for cancer cells (Sun et al., 2009).

Several studies have shown that berberine has anti-cancer potential by interfering with the multiple aspects of tumorigenesis and tumor progression in both in vitro and in vivo experiments. These observations have been well summarized in recent reports (Sun et al., 2009; Tan et al., 2011). Berberine inhibits the proliferation of multiple cancer cell lines by inducing cell-cycle arrest at the G1 or G 2 / M phases and by apoptosis (Sun et al., 2009; Eom et al., 2010; Burgeiro et al., 2011). In addition, berberine induces endoplasmic reticulum stress (Chang et al., 1990; Eom et al., 2010) and autophagy (Wang et al., 2010) in cancer cells.

However, compared with clinically prescribed anti-cancer drugs, the cytotoxic potency of berberine is much lower, with an IC50 generally at 10 µM to 100 µM depending on the cell type and treatment duration in vitro (Sun et al., 2009). Besides, berberine also induces morphologic differentiation in human teratocarcinoma (testes) cells (Chang et al., 1990).

Anti-metastatic

The effect of berberine on invasion, migration, metastasis, and angiogenesis is mediated through the inhibition of focal adhesion kinase (FAK), NF-κB, urokinase-type plasminogen-activator (u-PA), matrix metalloproteinase 2 (MMP-2), and matrix metalloproteinase 9 (MMP-9) (Ho et al., 2009; Hamsa & Kuttan. (2011); reduction of Rho kinase-mediated Ezrin phosphorylation (Tang et al., 2009); reduction of the expression of COX-2, prostaglandin E, and prostaglandin E receptors (Singh et al., 2011); down-regulation of hypoxia-inducible factor 1 (HIF-1), vascular endothelial growth factor (VEGF), pro-inflammatory mediators (Jie et al., 2011; Hamsa & Kuttan, 2012).

Hepatoma, Leukaemia

The cytotoxic effects of Coptis chinensis extracts and their major constituents on hepatoma and leukaemia cells in vitro have been investigated. Four human liver cancer cell lines, namely HepG2, Hep3B, SK-Hep1 and PLC/PRF/5, and four leukaemia cell lines, namely K562, U937, P3H1 and Raji, were investigated. C. chinensis exhibited strong activity against SK-Hep1 (IC50 = 7 microg/mL) and Raji (IC50 = 4 microg/mL) cell lines. Interestingly, the two major compounds of C. chinensis, berberine and coptisine, showed a strong inhibition on the proliferation of both hepatoma and leukaemia cell lines. These results suggest that the C. chinensis extract and its major constituents berberine and coptisine possess active anti-hepatoma and anti-leukaemia activities (Lin, 2004).

Leukemia

The steady-state level of nucleophosmin/B23 mRNA decreased during berberine-induced (25 g/ml, 24 to 96 hours) apoptosis of human leukemia HL-60 cells. A decline in telomerase activity was also observed in HL-60 cells treated with berberine. A stable clone of nucleophosmin/B23 over-expressed in HL-60 cells was selected and found to be less responsive to berberine-induced apoptosis. About 35% to 63% of control vector–transfected cells (pCR3) exhibited morphological characteristics of apoptosis, while about 8% to 45% of nucleophosmin/B23-over-expressed cells (pCR3-B23) became apoptotic after incubation with 15 g/ml berberine for 48 to 96 hours.

These results indicate that berberine-induced apoptosis is associated with the down-regulation of nucleophosmin/B23 and telomerase activity. Nucleophosmin/B23 may play an important role in the control of the cellular response to apoptosis induction (Hsing, 1999).

Prostate Cancer

In vitro treatment of androgen-insensitive (DU145 and PC-3) and androgen-sensitive (LNCaP) prostate cancer cells with berberine inhibited cell proliferation and induced cell death in a dose-dependent (10-100 micromol/L) and time-dependent (24–72 hours) manner. Berberine significantly (P < 0.05-0.001) enhanced apoptosis of DU145 and LNCaP cells with induction of a higher ratio of Bax/Bcl-2 proteins, disruption of mitochondrial membrane potential., and activation of caspase-9, caspase-3, and poly(ADP-ribose) polymerase.

The effectiveness of berberine in checking the growth of androgen-insensitive, as well as androgen-sensitive, prostate cancer cells without affecting the growth of normal prostate epithelial cells indicates that it may be a promising candidate for prostate cancer therapy (Mantena, 2006).

In another study, the treatment of human prostate cancer cells (PC-3) with berberine-induced dose-dependent apoptosis; however, this effect of berberine was not seen in non-neoplastic human prostate epithelial cells (PWR-1E). Berberine-induced apoptosis was associated with the disruption of the mitochondrial membrane potential., release of apoptogenic molecules (cytochrome c and Smac/DIABLO) from mitochondria and cleavage of caspase-9,-3 and PARP proteins.

Berberine-induced apoptosis was blocked in the presence of the anti-oxidant, N-acetylcysteine, through the prevention of disruption of mitochondrial membrane potential and subsequently release of cytochrome c and Smac/DIABLO. Taken together, these results suggest that the berberine-mediated cell death of human prostate cancer cells is regulated by reactive oxygen species, and therefore suggests that berberine may be considered for further studies as a promising therapeutic candidate for prostate cancer (Meeran, 2008).

Breast Cancer

DNA microarray technology has been used to understand the molecular mechanism underlying the anti-cancer effect of berberine carcinogenesis in two human breast cancer cell lines, the ER-positive MCF-7 and ER-negative MDA-MB-231 cells; specifically, whether it affects the expression of cancer-related genes. Treatment of the cancer cells with berberine markedly inhibited their proliferation in a dose- and time-dependent manner. The growth-inhibitory effect was much more profound in MCF-7 cell line than that in MDA-MB-231 cells.

IFN-β is among the most important anti-cancer cytokines, and the up-regulation of this gene by berberine is, at least in part, responsible for its anti-proliferative effect. The results of this study implicate berberine as a promising extract for chemoprevention and chemotherapy of certain cancers (Kang, 2005).

Breast Cancer Metastasis

Berberine also inhibits the growth of Anoikis-resistant MCF-7 and MDA-MB-231 breast cancer cell lines by inducing cell-cycle arrest. Anoikis, or detachment-induced apoptosis, may prevent cancer progression and metastasis by blocking signals necessary for survival of localized cancer cells. Resistance to anoikis is regarded as a prerequisite for metastasis; however, little is known about the role of berberine in anoikis-resistance.

The anoikis-resistant cells have a reduced growth rate and are more invasive than their respective adherent cell lines. The effect of berberine on growth was compared to that of doxorubicine, which is a drug commonly used to treat breast cancer, in both the adherent and anoikis-resistant cell lines. Berberine promoted the growth inhibition of anoikis-resistant cells to a greater extent than doxorubicine treatment. Treatment with berberine-induced cell-cycle arrest at G0/G1 in the anoikis-resistant MCF-7 and MDA-MB-231 cells was compared to untreated control cells. These results reveal that berberine can efficiently inhibit growth by inducing cell-cycle arrest in anoikis-resistant MCF-7 and MDA-MB-231 cells. Further analysis of these phenotypes is essential for understanding the effect of berberine on anoikis-resistant breast cancer cells, which would be relevant for the therapeutic targeting of breast cancer metastasis (Kim, 2010).

Melanoma

Berberine inhibits melanoma cancer cell migration by reducing the expressions of cyclooxygenase-2, prostaglandin E2 and prostaglandin E2 receptors. The effects and associated molecular mechanism of berberine on human melanoma cancer cell migration using melanoma cell lines A375 and Hs294 were probed in an in vitro cell migration assay, indicating that over- expression of cyclo-oxygenase (COX)-2, its metabolite prostaglandin E2 (PGE2) and PGE2 receptors promote the migration of cells.

Moreover, berberine inhibited the activation of nuclear factor-kappa B (NF-kB), an up- stream regulator of COX-2, in A375 cells, and treatment of cells with caffeic acid phenethyl ester, an inhibitor of NF-kB, inhibited cell migration. Together, these results indicate that berberine inhibits melanoma cell migration, an essential step in invasion and metastasis, by inhibition of COX-2, PGE2 and PGE2 receptors (Sing, 2011).

Cell-cycle Arrest, Squamous-cell Carcinoma

The in vitro treatment of human epidermoid carcinoma A431 cells with berberine decreases cell viability and induces cell death in a dose (5-75 microM)- and time (12–72 hours)-dependent manner, which was associated with an increase in G(1) arrest. G(0)/G(1) phase of the cell-cycle is known to be controlled by cyclin dependent kinases (Cdk), cyclin kinase inhibitors (Cdki) and cyclins.

Pre-treatment of A431 cells with the pan-caspase inhibitor (z-VAD-fmk) significantly blocked the berberine-induced apoptosis in A431 cells confirmed that berberine-induced apoptosis is mediated through activation of caspase 3-dependent pathway.

Together, these results indicate berberine as a chemotherapeutic agent against human epidermoid carcinoma A431 (squamous-cell) cells in vitro; further in vivo studies are required to determine whether berberine could be an effective chemotherapeutic agent for the management of non-melanoma skin cancers (Mantena, 2006).

Cervical Cancer, Radio-sensitizer

Cervical cancer remains one of the major killers amongst women worldwide. In India, a cisplatin based chemo/radiotherapy regimen is used for the treatment of advanced cervical cancer. Evidence shows that most of the chemotherapeutic drugs used in current clinical practice are radio-sensitizers. Natural products open a new avenue for treatment of cancer, as they are generally tolerated at high doses. Animal studies have confirmed the anti-tumorigenic activity of natural products, such as curcumin and berberine.

Berberine is a natural chemo-preventive agent, extracted from Berberis aristata, which has been shown to suppress and retard carcinogenesis by inhibiting inflammation.

The combined therapy of cisplatin/berberine and radiotherapy produced up-regulation of pro-apoptotic proteins Bax and p73, while causing down regulation of the anti-apoptotic proteins Bcl-xL, COX-2, cyclin D1. This additionally was accompanied by increased activity of caspase-9 and caspase-3, and reduction in telomerase activity. Results demonstrated that the treatment combination of berberine/cisplatin had increased induction of apoptosis relative to cisplatin alone (Komal., Singh, & Deshwal., 2013).

Anti-oxidative; Breast, Liver and Colon Cancer

The effect of B. vulgaris extract and berberine chloride on cellular thiobarbituric acid reactive species (TBARS) formation (lipid peroxidation), diphenyle–alpha-picrylhydrazyl (DPPH) oxidation, cellular nitric oxide (NO) radical scavenging capability, superoxide dismutase (SOD), glutathione peroxidase (GPx), acetylcholinesterase (AChE) and alpha-gulcosidase activities were spectrophotometrically determined.

Barberry crude extract contains 0.6 mg berberine/mg crude extract. Barberry extract showed potent anti-oxidative capacity through decreasing TBARS, NO and the oxidation of DPPH that is associated with GPx and SOD hyperactivation. Both berberine chloride and barberry ethanolic extract were shown to have inhibitory effect on the growth of breast, liver and colon cancer cell lines (MCF7, HepG2 and CACO-2, respectively) at different incubation times starting from 24 hours up to 72 hours and the inhibitory effect increased with time in a dose-dependent manner.

This work demonstrates the potential of the barberry crude extract and its active alkaloid, berberine, for suppressing lipid peroxidation, suggesting a promising use in the treatment of hepatic oxidative stress, Alzheimer and idiopathic male factor infertility. As well, berberis vulgaris ethanolic extract is a safe non-toxic extract as it does not inhibit the growth of PBMC that can induce cancer cell death (Abeer et al., 2013).

Source:

Alkaloids Isolated from Natural Herbs as the Anti-cancer Agents. Evidence-Based Complementary and Alternative Medicine. Volume 2012 (2012) http://dx.doi.org/10.1155/2012/485042

References

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Chang KSS, Gao C, Wang LC. (1990). Berberine-induced morphologic differentiation and down-regulation of c-Ki-ras2 protooncogene expression in human teratocarcinoma cells. Cancer Letters, 55(2):103–108.


Chen J, ZHao H, Wang X, et al. (2008). Analysis of major alkaloids in Rhizoma coptidis by capillary electrophoresis-electrospray-time of flight mass spectrometry with different background electrolytes. Electrophoresis, 29(10):2135–2147.


Eom KS, Kim HJ, So HS, et al. (2010). Berberine-induced apoptosis in human glioblastoma T98G Cells Is mediated by endoplasmic reticulum stress accompanying reactive oxygen species and mitochondrial dysfunction. Biological and Pharmaceutical Bulletin, 33(10):1644–1649.


El-Wahab AEA, Ghareeb DA, et al. (2013). In vitro biological assessment of berberis vulgaris and its active constituent, berberine: anti-oxidants, anti-acetylcholinesterase, anti-diabetic and anti-cancer effects. BMC Complementary and Alternative Medicine, 13:218 doi:10.1186/1472-6882-13-218


Hamsa TP & Kuttan G. (2011). Berberine inhibits pulmonary metastasis through down-regulation of MMP in metastatic B16F-10 melanoma cells. Phytotherapy Research, 26(4):568–578.


Hamsa TP & Kuttan G. (2012). Anti-angiogenic activity of berberine is mediated through the down-regulation of hypoxia-inducible factor-1, VEGF, and pro-inflammatory mediators. Drug and Chemical Toxicology, 35(1):57–70.


Han J, Lin H, Huang W. (2011). Modulating gut microbiota as an anti-diabetic mechanism of berberine. Medical Science Monitor, 17(7):RA164–RA167.


Ho YT, Yang JS, Li TC, et al. (2009). Berberine suppresses in vitro migration and invasion of human SCC-4 tongue squamous cancer cells through the inhibitions of FAK, IKK, NF-κB, u-PA and MMP-2 and -9. Cancer Letters, 279(2):155–162.


Hur JM, Hyun MS, Lim SY, Lee WY, Kim D. (2009). The combination of berberine and irradiation enhances anti-cancer effects via activation of p38 MAPK pathway and ROS generation in human hepatoma cells. Journal of Cellular Biochemistry, 107(5):955–964.


Islam MM & Kumar GS. (2009). RNA-binding potential of protoberberine alkaloids: spectroscopic and calorimetric studies on the binding of berberine, palmatine, and coralyne to protonated RNA structures. DNA and Cell Biology, 28(12):637–650.


Ji JB. (2011). Active Ingredients of Traditional Chinese Medicine: Pharmacology and Application, People's Medical Publishing House Cp., LTD.


Jie S, Li H, Tian Y, et al. (2011). Berberine inhibits angiogenic potential of Hep G2 cell line through VEGF down-regulation in vitro. Journal of Gastroenterology and Hepatology, 26(1):179–185.


Kang JX, Liu J, Wang J, He C, Li FP. (2005). The extract of huanglian, a medicinal herb, induces cell growth arrest and apoptosis by up-regulation of interferon-β and TNF-α in human breast cancer cells. Carcinogenesis, 26(11):1934-1939. doi:10.1093/carcin/bgi154


Kim JB, Yu JH, Ko E, et al. (2010). The alkaloid Berberine inhibits the growth of Anoikis-resistant MCF-7 and MDA-MB-231 breast cancer cell lines by inducing cell-cycle arrest. Phytomedicine, 17(6):436-40. doi: 10.1016/j.phymed.2009.08.012.


Komal Singh M, & Deshwal VK. (2013). Natural plant product berberine/cisplatin based radiotherapy for cervical cancer: The new and effective method to treat cervical cancer. Global Journal of Research on Medicinal Plants and Indigenous Medicine, 2(5), 278-291.


Kulkarni SK & Dhir A. (2010). Berberine: a plant alkaloid with therapeutic potential for central nervous system disorders. Phytotherapy Research, 24(3):317–324.


Lau CW, X. Q. Yao XQ, et al. (2001). Cardiovascular actions of berberine. Cardiovascular Drug Reviews, 19(3):234–244.


Li, XL Hu XJ, Wang H, et al. (2012). Molecular spectroscopy evidence for berberine binding to DNA: comparative binding and thermodynamic profile of intercalation. Biomacromolecules, 13(3):873–880.


Lin CC, Ng LT, Hsu FF, Shieh DE, Chiang LC. (2004). Cytotoxic effects of Coptis chinensis and Epimedium sagittatum extracts and their major constituents (berberine, coptisine and icariin) on hepatoma and leukaemia cell growth. Clin Exp Pharmacol Physiol, 31(1-2):65-9.


Mantena SK, Sharma SD, Katiyar SK. (2006). Berberine, a natural product, induces G1-phase cell-cycle arrest and caspase-3-dependent apoptosis in human prostate carcinoma cells. Mol Cancer Ther, 5(2):296-308. doi: 10.1158/1535-7163.MCT-05-0448


Mantena SK, Sharma SD, Katiyar SK. (2006). Berberine inhibits growth, induces G1 arrest and apoptosis in human epidermoid carcinoma A431 cells by regulating Cdki–Cdk-cyclin cascade, disruption of mitochondrial membrane potential and cleavage of caspase 3 and PARP. Carcinogenesis, 27(10):2018-27. doi: 10.1093/carcin/bgl043


Meeran SM, Katiyar S & Katiyar SK. (2008). Berberine-induced apoptosis in human prostate cancer cells is initiated by reactive oxygen species generation. Toxicology and Applied Pharmacology, 229(1):33-43. doi:10.1016/j.taap.2007.12.027


Singh T, Vaid M, Katiyar N, et al. (2011). Berberine, an isoquinoline alkaloid, inhibits melanoma cancer cell migration by reducing the expressions of cyclooxygenase-2, prostaglandin E and prostaglandin E receptors. Carcinogenesis, 32(1):86–92.


Sun Y, Xun K, Wang Y, Chen X. (2009). A systematic review of the anti-cancer properties of berberine, a natural product from Chinese herbs. Anti-Cancer Drugs, 20(9):757–769.


Tan W, Lu J, Huang M, et al. (2011). Anti-cancer natural products isolated from chinese medicinal herbs. Chinese Medicine, 6(1):27.


Tang F, Wang D, Duan C, et al. (2009) Berberine inhibits metastasis of nasopharyngeal carcinoma 5-8F cells by targeting rho kinase-mediated ezrin phosphorylation at threonine 567. Journal of Biological Chemistry, 284(40):27456–27466.


Wang N, Feng Y, Zhu M et al. (2010). Berberine induces autophagic cell death and mitochondrial apoptosis in liver cancer cells: the cellular mechanism. Journal of Cellular Biochemistry, 111(6):1426–1436.


Wu HL, Hsu CY, Liu WH, Yung BYM. (1999). Berberine‐induced apoptosis of human leukemia HL‐60 cells is associated with down‐regulation of nucleophosmin/B23 and telomerase activity. International Journal of Cancer, 81(6):923–929.


Youn MJ, So HS, Cho HJ, et al. (2008). Berberine, a natural product, combined with cisplatin enhanced apoptosis through a mitochondria/caspase-mediated pathway in HeLa cells. Biological and Pharmaceutical Bulletin, 31(5):789–795.


Yu HH, Kim KJ, Cha JD, et al. (2005). Antimicrobial activity of berberine alone and in combination with ampicillin or oxacillin against methicillin-resistant Staphylococcus aureus. Journal of Medicinal Food, 8(4):454–461.

anti-apoptotic, Anti-cancer, anti-inflammatory, Anti-metastatic, anti-proliferative, anti-tumor, apoptosis, Apoptotic, Autophagy, BAX, Bcl-2, Breast cancer, cancer stem cells, cell-cycle arrest, Chapter 8 Injectables and Cancer Research, Chemotherapy, Colon Cancer or Colorectal cancer, CSCs, EpCAM, Esophageal cancer, FAK, G0/G1, G1, G2/M, Glioblastoma, induces apoptosis, Leukemia, Liver cancer, metastasis, Ovarian cancer, p21, p53, Prostate cancer, Prostate cancer cell lines, Rabdosia rubescens, Rectal cancer, TrxR

Oridonin

Cancer: Prostate

Action: Growth arrest, autophagy

To investigate the mechanism of oridonin (ORI)-induced autophagy in prostate cancer PC-3 cells, PC-3 cells cultured in vitro were treated with ORI, and the inhibitory ratio of ORI on PC-3 cells was assayed by 3-4,5- dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide. After ORI treatment, the proliferation of PC-3 cells was inhibited significantly in a concentration and time-dependent manner. SEM examination revealed cellular shrinkage and disappearance of surface microvilli in ORI-treated cells. Under TEM examination, the nuclei exhibited chromatin condensation and the appearance of a large number of autophagosomes with double-membrane structure in cytoplasm. AO staining showed the existence of AVOs. The expression of LC3 and the mRNA level of beclin 1 was increased by ORI. Furthermore, autophagy inhibitor 3-methyladenine reversed the increase of beclin 1 mRNA. The growth of PC-3 cells was inhibited, and autophagy was induced by ORI, indicating ORI may have a potential antitumor effect.

Source
Ye LH, Li WJ, Jiang XQ, et al. Study on the autophagy of prostate cancer PC-3 cells induced by oridonin. Anat Rec (Hoboken). 2012 Mar;295(3):417-22. doi: 10.1002/ar.21528.

 

Cancer: Multiple myeloma

Action: Inhibits proliferation and induces apoptosis

This study was purposed to investigate the antitumor effect of oridonin on human multiple myeloma cell line U266 The results showed that the oridonin obviously inhibited the growth of U266 cell in dose-and time-dependent manners. As for morphological changes, characteristic apoptotic cells presented in U266 cells treated with 10 µmol/L oridonin for 24 hours. The apoptotic rate of U266 cells increased in dose and time dependent manners; after treatment of U266 cells with oridonin the mRNA levels of FGFR3, BCL2, CCND1 and MYC as well as the their protein levels decreased. Occasionally, the oridonin up-regulated the protein levels of P53 in the same manner. It is concluded that the oridonin can exert its anti-tumor effect by inhibiting proliferation and inducing apoptosis of U266 cell in dose dependent and time dependent manners, that maybe give the clues about new program of target therapy for multiple myeloma.

Source:

Duan HQ, Li MY, Gao L, et al. Mechanism concerning antitumor effect of oridonin on multiple myeloma cell line U266. Zhongguo Shi Yan Xue Ye Xue Za Zhi. 2014 Apr;22(2):364-9. doi: 10.7534/j.issn.1009-2137.2014.02.018.

Cancer: Multiple myeloma

Action: Induces apoptosis and autophagy

Exposure to oridonin (1-64 μmol/L) inhibited the proliferation of RPMI8266 cells in a concentration-dependent manner with an IC(50) value of 6.74 μmol/L. Exposure to oridonin (7 μmol/L) simultaneously induced caspase 3-mediated apoptosis and Beclin 1-dependent autophagy of RPMI8266 cells. Both the apoptosis and autophagy were time-dependent, and apoptosis was the main effector pathway of cell death. Exposure to oridonin (7 μmol/L) increased intracellular ROS and reduced SIRT1 nuclear protein in a time-dependent manner.

Oridonin simultaneously induces apoptosis and autophagy of human multiple myeloma RPMI8266 cells via regulation of intracellular ROS generation and SIRT1 nuclear protein. The cytotoxicity of oridonin is mainly mediated through the apoptotic pathway, whereas the autophagy protects the cells from apoptosis.

Source

Zeng R, Chen Y, Zhao S, Cui GH.Autophagy counteracts apoptosis in human multiple myeloma cells exposed to oridonin in vitro via regulating intracellular ROS and SIRT1. Acta Pharmacol Sin. 2012 Jan;33(1):91-100. doi: 10.1038/aps.2011.143.

Cancer: Prostate, acute promyelocytic leukemia, breast, non-small-cell lung (NSCL), Ehrlich ascites, P388 lymphocytic leukemia, colorectal., ovarian, esphageal

Action: Chemoresistance, Ara-C, VP-16 

Cancer cell arises in part through the acquisition of apoptotic resistance. Leukemia cells resistant to chemotherapy-induced apoptosis have been found to be sensitive to oridonin, a natural agent with potent anticancer activity. Weng et al., (2014) compared the response of human leukemia cells with oridonin and the antileukemia drugs Ara-C and VP-16. Compared with HL60 cells, K562 and K562/ADR cells displayed resistance to apoptosis stimulated by Ara-C and VP-16 but sensitivity to oridonin. Mechanistic investigations revealed that oridonin upregulated BIM-S by diminishing the expression of miR-17 and miR-20a, leading to mitochondria-dependent apoptosis. In contrast, neither Ara-C nor VP-16 could reduce miR-17 and miR-20a expression or could trigger BIM-S–mediated apoptosis.

Notably, silencing miR-17 or miR-20a expression by treatment with microRNA (miRNA; miR) inhibitors or oridonin restored sensitivity of K562 cells to VP-16. Synergistic effects of oridonin and VP-16 were documented in cultured cells as well as mouse tumor xenograft assays. Inhibiting miR-17 or miR-20a also augmented the proapoptotic activity of oridonin. Taken together, our results identify a miRNA-dependent mechanism underlying the anticancer effect of oridonin and provide a rationale for its combination with chemotherapy drugs in addressing chemoresistant leukemia cells.

Reference

Weng Hy, Huang Hl, Dong B, et al. Inhibition of miR-17 and miR-20a by Oridonin Triggers Apoptosis and Reverses Chemoresistance by Derepressing BIM-S. Cancer Res; 74(16); 1–11. doi: 10.1158/0008-5472.CAN-13-1748

Action: Induces apoptosis

Oridonin is a tetracycline diterpenoid isolated from the plant Rabdosia rubescens (RR) [(Hemsl.). Hara (Lamiaceae)] (dong ling cao) is a Chinese medicinal herb used widely in provinces including Henan. The aerial parts of RR and other species of the same genus has been reported to have the functions of clearing “heat” and “toxicity”, nourishing “yin”, removing “blood stasis”, and relieving swelling. RR has been used to treat stomach-ache, sore throat and cough.

Gastric Cancer, Esophageal Cancer, Liver Cancer, Prostate Cancer

RR and its extracts have been shown to be able to suppress disease progress, reduce tumor burden, alleviate syndrome and prolong survival in patients with gastric carcinoma, esophageal., liver and prostate cancers (Tang & Eisenbrand, 1992). Interestingly, other Isodon plants including Isodon japonicus Hara (IJ) and I. trichocarpus (IT) are also applied as home remedies for similar disorders in Japan and Korea.

Induces Apoptosis

These reports suggest that Isodon plants should have at least one essential anti-tumor component. In the 1970s, a bitter tetracycline diterpenoid compound, oridonin, was isolated from RR, IJ, and IT separately, and was shown to be a potent apoptosis inducer in a variety of cancer cells (Fujita et al., 1970; Fujita et al., 1976; Henan Medical Institute, 1978; Fujita et al., 1988).

Anti-cancer

There is currently research being undertaken regarding the relationship between the chemical structure/modifications and the molecular mechanisms underlying its anti-cancer activity, such as suppression of tumor proliferation and induction of tumor cell death, and the cell signal transduction in anti-cancer activity of oridonin (Zhang et al., 2010).

Prostate Cancer, Breast Cancer, NSCLC, Leukemia, Glioblastoma

Oridonin has been found to effectively inhibit the proliferation of a wide variety of cancer cells including those from prostate (LNCaP, DU145, PC3), breast (MCF-7, MDA-MB231), non-small-cell lung (NSCL) (NCI-H520, NCI-H460, NCI-H1299) cancers, acute promyelocytic leukemia (NB4), and glioblastoma multiforme (U118, U138).

Oridonin induced apoptosis and G0/G1 cell-cycle arrest in LNCaP prostate cancer cells. In addition, expression of p21waf1 was induced in a p53-dependent manner. Taken together, oridonin inhibited the proliferation of cancer cells via apoptosis and cell-cycle arrest with p53 playing a central role in several cancer types which express the wild-type p53 gene. Oridonin may be a novel, adjunctive therapy for a large variety of malignancies (Ikezoe et al., 2003).

Breast Cancer; Anti-metastatic

According to the flow cytometric analysis, oridonin suppressed MCF-7 cell growth by cell-cycle arrest at the G2/M phase and caused accumulation of MDA-MB-231 cells in the Sub-G1 phase. The induced apoptotic effect of oridonin was further confirmed by a morphologic characteristics assay and TUNEL assay. Meanwhile, oridonin significantly suppressed MDA-MB-231 cell migration and invasion, decreased MMP-2/MMP-9 activation and inhibited the expression of Integrin β1 and FAK. In conclusion, oridonin inhibited growth and induced apoptosis in breast cancer cells, which might be related to DNA damage and activation of intrinsic or extrinsic apoptotic pathways. Moreover, oridonin also inhibited tumor invasion and metastasis in vitro possibly via decreasing the expression of MMPs and regulating the Integrin β1/FAK pathway in MDA-MB-231 cells (Wang et al., 2013).

Gastric Cancer

The inhibitory effect of oridonin on gastric cancer HGC-27 cells was detected using the 3-(4, 5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide assay. After treated with oridonin (0, 1.25, 2.5, 5 and 10 µg/mL), HGC-27 cells were collected for anexin V-phycoerythrin and 7-amino-actinomycin D double staining and tested by flow cytometric analysis, and oridonin- induced apoptosis in HGC-27 cells was detected.

Oridonin significantly inhibited the proliferation of HGC-27 cells in a dose- and time-dependent manner. The inhibition rates of HGC-27 treated with four different concentrations of oridonin for 24 h (1.25, 2.5, 5 and 10 µg/mL) were 1.78% ± 0.36%, 4.96% ± 1.59%, 10.35% ± 2.76% and 41.6% ± 4.29%, respectively, which showed a significant difference (P < 0.05. Cells treated with oridonin showed typical apoptotic features with acridine orange/ethidium bromide staining. After treatment with oridonin, the cells became round, shrank, and developed small buds around the nuclear membrane while forming apoptotic bodies. However, the change in the release of LDH caused by necrosis was insignificant, suggesting that the major cause of oridonin-induced HGC-27 cell death was apoptosis. Flow cytometric analysis also revealed that oridonin induced significant apoptosis compared with the controls (P < 0.05).

Apoptosis of HGC-27 induced by oridonin may be associated with differential expression of Apaf-1, caspase-3 and cytochrome c, which are highly dependent upon the mitochondrial pathway (Sun et al., 2012).

Ehrlich Ascites, Leukemia

Oridonin has been found to also increase lifespan of mice bearing Ehrlich ascites or P388 lymphocytic leukemia. Oridonin triggered apoptosis in more than 50% of t(8;21) leukemic cells in vitro at concentration of 2 M or higher accompanied by degradation of AE oncoprotein, and showed significant anti-leukemia efficacies with low adverse effects in vivo. These data suggest possible beneficial effects for patients with t(8;21) acute myeloid leukemia (AML) (Zhou et al., 2007).

Prostate Cancer, Breast Cancer, Ovarian Cancer

Oridonin exhibited anti-proliferative activity toward all cancer cell lines tested, with an IC50 estimated by the MTT cell viability assay ranging from 5.8+/-2.3 to 11.72+/-4.8 microM. The increased incidence of apoptosis, identified by characteristic changes in cell morphology, was seen in tumor lines treated with oridonin. Notably, at concentrations that induced apoptosis among tumor cells, oridonin failed to induce apoptosis in cultures of normal human fibroblasts. Oridonin up-regulated p53 and Bax and down-regulated Bcl-2 expression in a dose-dependent manner and its absorption spectrum was measured in the presence and absence of double stranded (ds) DNA. Oridonin inhibits cancer cell growth in a cell-cycle specific manner and shifts the balance between pro- and anti-apoptotic proteins in favor of apoptosis. The present data suggest that further studies are warranted to assess the potential of oridonin in cancer prevention and/or treatment (Chen et al., 2005).

Ovarian Cancer Stem Cells; Chemotherapy Resistance

Oridonin was suggested to suppress ovarian CSCs as is reflected by down-regulation of the surface marker EpCAM. Unlike NSAIDS (non-steroid anti-inflammatory drugs), well documented clinical data for phyto-active compounds are lacking. In order to evaluate objectively the potential benefit of these types of compounds in the treatment of ovarian cancer, strategically designed, large scale studies are warranted (Chen et al., 2012).

Colorectal Cancer

Oridonin induced potent growth inhibition, cell-cycle arrest, apoptosis, senescence and colony-forming inhibition in three colorectal cancer cell lines in a dose-dependent manner in vitro. Daily i.p. injection of oridonin (6.25, 12.5 or 25 mg/kg) for 28 days significantly inhibited the growth of SW1116 s.c. xenografts in BABL/C nude mice.

Oridonin possesses potent in vitro and in vivo anti-colorectal cancer activities that correlated with induction of histone hyperacetylation and regulation of pathways critical for maintaining growth inhibition and cell-cycle arrest. Therefore, oridonin may represent a novel therapeutic option in colorectal cancer treatment as it has been shown to induce apoptosis and senescence of colon cancer cells in vitro and in vivo (Gao et al., 2010).

Colon Cancer; Apoptosis

Oridonin increased intracellular hydrogen peroxide levels and reduced the glutathione content in a dose-dependent manner. N-acetylcysteine, a reactive oxygen species scavenger, not only blocked the oridonin-induced increase in hydrogen peroxide and glutathione depletion, but also blocked apoptosis and senescence induced by oridonin.

Moreover, exogenous catalase could inhibit the increase in hydrogen peroxide and apoptosis induced by oridonin, but not the glutathione depletion and senescence. Furthermore, thioredoxin reductase (TrxR) activity was reduced by oridonin in vitro and in cells, which may cause the increase in hydrogen peroxide. In conclusion, the increase in hydrogen peroxide and glutathione depletion account for oridonin-induced apoptosis and senescence in colorectal cancer cells, and TrxR inhibition is involved in this process.

Given the importance of TrxR as a novel cancer target in colon cancer, oridonin would be a promising clinical candidate (Gao et al., 2012).

Prostate Cancer; Apoptosis

Oridonin (ORI) could inhibit the proliferation and induce apoptosis in various cancer cell lines. After ORI treatment, the proliferations of human prostate cancer (HPC) cell lines PC-3 and LNCaP were inhibited in a concentration and time-dependent manner. ORI induced cell-cycle arrest at the G2/M phase. Autophagy occurred before the onset of apoptosis and protected cancer cells in ORI-treated HPC cells. P21 was involved in ORI-induced autophagy and apoptosis (Li et al., 2012).

References

Chen S, Gao J, Halicka HD, et al. (2005). The cytostatic and cytotoxic effects of oridonin (Rubescenin), a diterpenoid from Rabdosia rubescens, on tumor cells of different lineage. Int J Oncol, 26(3):579-88.

 

Chen SS, Michael A, Butler-Manuel SA. (2012). Advances in the treatment of ovarian cancer: a potential role of anti-inflammatory phytochemicals. Discov Med, 13(68):7-17.

 

Fujita E, Fujita T, Katayama H, Shibuya M. (1970). Terpenoids. Part XV. Structure and absolute configuration of oridonin isolated from Isodon japonicus trichocarpus. J Chem Soc (Chem Comm), 21:1674–1681

 

Fujita E, Nagao Y, Node M, et al. (1976). Anti-tumor activity of the Isodon diterpenoids: structural requirements for the activity. Experientia, 32:203–206.

 

Fujita T, Takeda Y, Sun HD, et al. (1988). Cytotoxic and anti-tumor activities of Rabdosia diterpenoids. Planta Med, 54:414–417.

 

Henan Medical Institute, Henan Medical College, Yunnan Institute of Botany. (1978). Oridonin–a new anti-tumor subject. Chin Science Bull, 23:53–56.

 

Ikezoe T, Chen SS, Tong XJ, et al. (2003). Oridonin induces growth inhibition and apoptosis of a variety of human cancer cells. Int J Oncol, 23(4):1187-93.

 

Gao FH, Hu XH, Li W, Liu H, et al. (2010). Oridonin induces apoptosis and senescence in colorectal cancer cells by increasing histone hyperacetylation and regulation of p16, p21, p27 and c-myc. BMC Cancer, 10:610. doi: 10.1186/1471-2407-10-610.

 

Gao FH, Liu F, Wei W, et al. (2012). Oridonin induces apoptosis and senescence by increasing hydrogen peroxide and glutathione depletion in colorectal cancer cells. Int J Mol Med, 29(4):649-55. doi: 10.3892/ijmm.2012.895.

 

Li X, Li X, Wang J, Ye Z, Li JC. (2012) Oridonin up-regulates expression of P21 and induces autophagy and apoptosis in human prostate cancer cells. Int J Biol Sci. 2012;8(6):901-12. doi: 10.7150/ijbs.4554.

 

Sun KW, Ma YY, Guan TP, et al. (2012). Oridonin induces apoptosis in gastric cancer through Apaf-1, cytochrome c and caspase-3 signaling pathway. World J Gastroenterol, 18(48):7166-74. doi: 10.3748/wjg.v18.i48.7166.

 

Tang W, Eisenbrand G. (1992). Chinese drugs of plant origin: chemistry, pharmacology, and use in traditional and modern medicine. Berlin: Springer-Verlag, 817–847.

 

Wang S, Zhong Z, Wan J, et al. (2013). Oridonin induces apoptosis, inhibits migration and invasion on highly-metastatic human breast cancer cells. Am J Chin Med, 41(1):177-96. doi: 10.1142/S0192415X13500134.

 

Zhang Wj, Huang Ql, Hua Z-C. (2010). Oridonin: A promising anti-cancer drug from China. Frontiers in Biology, 5(6):540-545.

 

Zhou G-B, Kang H, Wang L, et al. (2007). Oridonin, a diterpenoid extracted from medicinal herbs, targets AML1-ETO fusion protein and shows potent anti-tumor activity with low adverse effects on t(8;21) leukemia in vitro and in vivo. Blood, 109(8):3441-3450.

A2780 and PTX10, anti-apoptotic, Anti-cancer, Anti-cancer effect, anti-inflammatory, anti-tumor, apoptosis, Apoptotic, Autophagy, BAX, Bcl-2, Breast cancer, cell-cycle arrest, Chapter 7 Isolates and Cancer Research, Colon Cancer or Colorectal cancer, CSC, CSCs, DU-145, LNCaP, EpCAM, FAK, G0/G1, G1, G2/M, Glioblastoma, HGC-27, LNCaP, DU145, PC-3, MCF-7, MCF-7, MDA-MB231, MDA-MB-231, metastasis, NB4, NCI-H520, NCI-H460, NCI-H1299, Ovarian cancer, p21, P388, p53, PC3 and LNCaP, Prostate cancer, Rabdosia rubescens, Rectal cancer, S, SW1116 cells, TrxR, U118, U138

Oridonin

Cancer: Prostate, acute promyelocytic leukemia, breast, non-small-cell lung (NSCL), Ehrlich ascites, P388 lymphocytic leukemia, colorectal., ovarian, esphageal

Action: Induces apoptosis

Oridonin is a tetracycline diterpenoid isolated from the plant Rabdosia rubescens (RR) [(Hemsl.). Hara (Lamiaceae)] (dong ling cao) is a Chinese medicinal herb used widely in provinces including Henan. The aerial parts of RR and other species of the same genus has been reported to have the functions of clearing “heat” and “toxicity”, nourishing “yin”, removing “blood stasis”, and relieving swelling. RR has been used to treat stomach-ache, sore throat and cough.

Gastric Cancer, Esophageal Cancer, Liver Cancer, Prostate Cancer

RR and its extracts have been shown to be able to suppress disease progress, reduce tumor burden, alleviate syndrome and prolong survival in patients with gastric carcinoma, esophageal., liver and prostate cancers (Tang & Eisenbrand, 1992). Interestingly, other Isodon plants including Isodon japonicus Hara (IJ) and I. trichocarpus (IT) are also applied as home remedies for similar disorders in Japan and Korea.

Induces Apoptosis

These reports suggest that Isodon plants should have at least one essential anti-tumor component. In the 1970s, a bitter tetracycline diterpenoid compound, oridonin, was isolated from RR, IJ, and IT separately, and was shown to be a potent apoptosis inducer in a variety of cancer cells (Fujita et al., 1970; Fujita et al., 1976; Henan Medical Institute, 1978; Fujita et al., 1988).

Anti-cancer

There is currently research being undertaken regarding the relationship between the chemical structure/modifications and the molecular mechanisms underlying its anti-cancer activity, such as suppression of tumor proliferation and induction of tumor cell death, and the cell signal transduction in anti-cancer activity of oridonin (Zhang et al., 2010).

Prostate Cancer, Breast Cancer, NSCLC, Leukemia, Glioblastoma

Oridonin has been found to effectively inhibit the proliferation of a wide variety of cancer cells including those from prostate (LNCaP, DU145, PC3), breast (MCF-7, MDA-MB231), non-small-cell lung (NSCL) (NCI-H520, NCI-H460, NCI-H1299) cancers, acute promyelocytic leukemia (NB4), and glioblastoma multiforme (U118, U138).

Oridonin induced apoptosis and G0/G1 cell-cycle arrest in LNCaP prostate cancer cells. In addition, expression of p21waf1 was induced in a p53-dependent manner. Taken together, oridonin inhibited the proliferation of cancer cells via apoptosis and cell-cycle arrest with p53 playing a central role in several cancer types which express the wild-type p53 gene. Oridonin may be a novel, adjunctive therapy for a large variety of malignancies (Ikezoe et al., 2003).

Breast Cancer; Anti-metastatic

According to the flow cytometric analysis, oridonin suppressed MCF-7 cell growth by cell-cycle arrest at the G2/M phase and caused accumulation of MDA-MB-231 cells in the Sub-G1 phase. The induced apoptotic effect of oridonin was further confirmed by a morphologic characteristics assay and TUNEL assay. Meanwhile, oridonin significantly suppressed MDA-MB-231 cell migration and invasion, decreased MMP-2/MMP-9 activation and inhibited the expression of Integrin β1 and FAK. In conclusion, oridonin inhibited growth and induced apoptosis in breast cancer cells, which might be related to DNA damage and activation of intrinsic or extrinsic apoptotic pathways. Moreover, oridonin also inhibited tumor invasion and metastasis in vitro possibly via decreasing the expression of MMPs and regulating the Integrin β1/FAK pathway in MDA-MB-231 cells (Wang et al., 2013).

Gastric Cancer

The inhibitory effect of oridonin on gastric cancer HGC-27 cells was detected using the 3-(4, 5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide assay. After treated with oridonin (0, 1.25, 2.5, 5 and 10 µg/mL), HGC-27 cells were collected for anexin V-phycoerythrin and 7-amino-actinomycin D double staining and tested by flow cytometric analysis, and oridonin- induced apoptosis in HGC-27 cells was detected.

Oridonin significantly inhibited the proliferation of HGC-27 cells in a dose- and time-dependent manner. The inhibition rates of HGC-27 treated with four different concentrations of oridonin for 24 h (1.25, 2.5, 5 and 10 µg/mL) were 1.78% ± 0.36%, 4.96% ± 1.59%, 10.35% ± 2.76% and 41.6% ± 4.29%, respectively, which showed a significant difference (P < 0.05. Cells treated with oridonin showed typical apoptotic features with acridine orange/ethidium bromide staining. After treatment with oridonin, the cells became round, shrank, and developed small buds around the nuclear membrane while forming apoptotic bodies. However, the change in the release of LDH caused by necrosis was insignificant, suggesting that the major cause of oridonin-induced HGC-27 cell death was apoptosis. Flow cytometric analysis also revealed that oridonin induced significant apoptosis compared with the controls (P < 0.05).

Apoptosis of HGC-27 induced by oridonin may be associated with differential expression of Apaf-1, caspase-3 and cytochrome c, which are highly dependent upon the mitochondrial pathway (Sun et al., 2012).

Ehrlich Ascites, Leukemia

Oridonin has been found to also increase lifespan of mice bearing Ehrlich ascites or P388 lymphocytic leukemia. Oridonin triggered apoptosis in more than 50% of t(8;21) leukemic cells in vitro at concentration of 2 M or higher accompanied by degradation of AE oncoprotein, and showed significant anti-leukemia efficacies with low adverse effects in vivo. These data suggest possible beneficial effects for patients with t(8;21) acute myeloid leukemia (AML) (Zhou et al., 2007).

Prostate Cancer, Breast Cancer, Ovarian Cancer

Oridonin exhibited anti-proliferative activity toward all cancer cell lines tested, with an IC50 estimated by the MTT cell viability assay ranging from 5.8+/-2.3 to 11.72+/-4.8 microM. The increased incidence of apoptosis, identified by characteristic changes in cell morphology, was seen in tumor lines treated with oridonin. Notably, at concentrations that induced apoptosis among tumor cells, oridonin failed to induce apoptosis in cultures of normal human fibroblasts. Oridonin up-regulated p53 and Bax and down-regulated Bcl-2 expression in a dose-dependent manner and its absorption spectrum was measured in the presence and absence of double stranded (ds) DNA. Oridonin inhibits cancer cell growth in a cell-cycle specific manner and shifts the balance between pro- and anti-apoptotic proteins in favor of apoptosis. The present data suggest that further studies are warranted to assess the potential of oridonin in cancer prevention and/or treatment (Chen et al., 2005).

Ovarian Cancer Stem Cells; Chemotherapy Resistance

Oridonin was suggested to suppress ovarian CSCs as is reflected by down-regulation of the surface marker EpCAM. Unlike NSAIDS (non-steroid anti-inflammatory drugs), well documented clinical data for phyto-active compounds are lacking. In order to evaluate objectively the potential benefit of these types of compounds in the treatment of ovarian cancer, strategically designed, large scale studies are warranted (Chen et al., 2012).

Colorectal Cancer

Oridonin induced potent growth inhibition, cell-cycle arrest, apoptosis, senescence and colony-forming inhibition in three colorectal cancer cell lines in a dose-dependent manner in vitro. Daily i.p. injection of oridonin (6.25, 12.5 or 25 mg/kg) for 28 days significantly inhibited the growth of SW1116 s.c. xenografts in BABL/C nude mice.

Oridonin possesses potent in vitro and in vivo anti-colorectal cancer activities that correlated with induction of histone hyperacetylation and regulation of pathways critical for maintaining growth inhibition and cell-cycle arrest. Therefore, oridonin may represent a novel therapeutic option in colorectal cancer treatment as it has been shown to induce apoptosis and senescence of colon cancer cells in vitro and in vivo (Gao et al., 2010).

Colon Cancer; Apoptosis

Oridonin increased intracellular hydrogen peroxide levels and reduced the glutathione content in a dose-dependent manner. N-acetylcysteine, a reactive oxygen species scavenger, not only blocked the oridonin-induced increase in hydrogen peroxide and glutathione depletion, but also blocked apoptosis and senescence induced by oridonin.

Moreover, exogenous catalase could inhibit the increase in hydrogen peroxide and apoptosis induced by oridonin, but not the glutathione depletion and senescence. Furthermore, thioredoxin reductase (TrxR) activity was reduced by oridonin in vitro and in cells, which may cause the increase in hydrogen peroxide. In conclusion, the increase in hydrogen peroxide and glutathione depletion account for oridonin-induced apoptosis and senescence in colorectal cancer cells, and TrxR inhibition is involved in this process.

Given the importance of TrxR as a novel cancer target in colon cancer, oridonin would be a promising clinical candidate (Gao et al., 2012).

Prostate Cancer; Apoptosis

Oridonin (ORI) could inhibit the proliferation and induce apoptosis in various cancer cell lines. After ORI treatment, the proliferations of human prostate cancer (HPC) cell lines PC-3 and LNCaP were inhibited in a concentration and time-dependent manner. ORI induced cell-cycle arrest at the G2/M phase. Autophagy occurred before the onset of apoptosis and protected cancer cells in ORI-treated HPC cells. P21 was involved in ORI-induced autophagy and apoptosis (Li et al., 2012).

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