Category Archives: JAK2

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.

anti-proliferative, anti-proliferative effect, anti-tumor, apoptosis, Bcl-xL, Breast cancer, cell-cycle arrest, Chapter 7 Isolates and Cancer Research, G2/M, induces apoptosis, JAK2, JNK, MDA-MB-231, p53, Pancreatic cancer, STAT3

Cucurbitacin D (CuD) (See also Trichosanthin)

Cancer: Hepatocellular carcinoma, pancreatic, breast

Action: Apoptosis

Breast Cancer

Cucurbitacin D (CuD) isolated from Trichosanthes kirilowii induces apoptosis in several cancer cells. Constitutive signal transducer and activator of transcription 3 (STAT3), which is an oncogenic transcription factor, is often observed in many human malignant tumors, including breast cancer. Kim et al. (2013) tested whether Trichosanthes kirilowii ethanol extract (TKE) or CuD suppresses cell growth and induces apoptosis through inhibition of STAT3 activity in breast cancer cells.

They found that both TKE and CuD suppressed proliferation and induced apoptosis and G2/M cell-cycle arrest in MDA-MB-231 breast cancer cells by inhibiting STAT3 phosphorylation. In addition, both TKE and CuD inhibited nuclear translocation and transcriptional activity of STAT3. Taken together, our results indicate that TKE and its derived compound, CuD, could be potent therapeutic agents for breast cancer, blocking tumor cell proliferation and inducing apoptosis through suppression of STAT3 activity.

Hepatocellular Carcinoma

Takahashi et al. (2009) found that the anti-tumor components isolated from the extract of trichosanthes (EOT) are cucurbitacin D and dihydrocucurbitacin D, and suggest that cucurbitacin D induces apoptosis through caspase-3 and phosphorylation of JNK in hepatocellular carcinoma cells. These results suggest that cucurbitacin D isolated from Trichosanthes kirilowii could be a valuable candidate for an anti-tumor drug.

Pancreatic Cancer

Dose-response studies showed that the drug inhibited 50% growth of seven pancreatic cancer cell lines at 10−7 mol/L, whereas clonogenic growth was significantly inhibited at 5 × 10−8 mol/L. Cucurbitacin B caused dose- and time-dependent G2-M-phase arrest and apoptosis of pancreatic cancer cells. This was associated with inhibition of activated JAK2, STAT3, and STAT5, increased level of p21WAF1 even in cells with nonfunctional p53, and decrease of expression of cyclin A, cyclin B1, and Bcl-XL with subsequent activation of the caspase cascade.

Cucurbitacin B has profound in vitro and in vivo anti-proliferative effects against human pancreatic cancer cells, and the compound may potentate the anti-proliferative effect of the chemotherapeutic agent gemcitabine. Further clinical studies are necessary to confirm our findings in patients with pancreatic cancer (Thoennissen et al., 2009).

References

Kim SR, Seo HS, Choi H-S, et al. (2013). Trichosanthes kirilowii Ethanol Extract and Cucurbitacin D Inhibit Cell Growth and Induce Apoptosis through Inhibition of STAT3 Activity in Breast Cancer Cells. Evidence-Based Complementary and Alternative Medicine, 2013. http://dx.doi.org/10.1155/2013/975350


Thoennissen NH, Iwanski GB, Doan NB, et al. (2009). Cucurbitacin B Induces Apoptosis by Inhibition of the JAK/STAT Pathway and Potentiates Anti-proliferative Effects of Gemcitabine on Pancreatic Cancer Cells.   Cancer Res, 69; 5876 doi: 10.1158/0008-5472.CAN-09-0536


Takahashi N, Yoshida Y, Sugiura T, et al. (2009). Cucurbitacin D isolated from Trichosanthes kirilowii induces apoptosis in human hepatocellular carcinoma cells in vitro. International Immunopharmacology, 9(4):508–513.

Angelica gigas, Angelica gigas (Nakai), angiogenesis, anti-tumor, apoptosis, Apoptotic, AR, Breast cancer, cell-cycle arrest, Chapter 8 Injectables and Cancer Research, Fibrosarcoma, IL-8, inflammation, JAK2, MDR, MTOR, p53, PARP, Pro-apoptotic, Prostate cancer, Sarcoma, STAT3, TNF

Decursin

Cancer: Prostate, breast, fibrosarcoma, sarcoma

Action: MDR, inflammation, anti-cancer, angiogenesis

Decursin is isolated from Angelica gigas (Nakai).

Angelica gigas NAKAI is used to treat dysmenorrhea, amenorrhea, menopause, abdominal pain, injuries, migraine, and arthritis. The physicochemical and toxicological characterization of compounds in A. gigas NAKAI, decursin, decursinol angelate, diketone decursin, ether decursin, epoxide decursin and oxim decursin, have been extensively studied (Mahat et al., 2012).

Sarcoma; Anti-cancer

The in vivo anti-tumor activities of decursinol angelate (1) and decursin (2) isolated from the roots of Angelica gigas were investigated. These two compounds, when administered consecutively for 9 days at 50 and 100 mg/kg i.p. in mice, caused a significant increase in the life span and a significant decrease in the tumor weight and volume of mice inoculated with Sarcoma-180 tumor cells. These results suggest that decursinol angelate (1) and decursin (2) from A. gigas have anti-tumor activities (Lee et al., 2003).

Fibrosarcoma

Decursin and related coumarin compounds in herbal extracts have a number of biological activities against inflammation, angiogenesis and cancer. The human fibrosarcoma cell line, HT1080, was treated with TNFα (tumor necrosis factor α) in the presence or absence of CSL-32. Treatment of HT1080 cells with a derivative of decursin (CSL-32) inhibited their proliferation, without affecting cell viability, and TNF α-induced expression of pro-inflammatory mediators, such as MMP-9 (matrix metalloproteinase-9) and IL-8 (interleukin-8) (Lee et al., 2012).

Prostate Cancer

Androgen and androgen receptor (AR) signaling are crucial for the genesis of prostate cancer (PCa), which can often develop into androgen-ligand-independent diseases that are lethal to patients. As current chemotherapy is largely ineffective for PCa and has serious toxic side-effects, a collaborative effort has been initiated to identify and develop novel, safe and naturally occurring agents that target AR signaling from Oriental medicinal herbs for the chemoprevention and treatment of PCa. The discovery of decursin from an Oriental formula containing Korean Angelica gigas Nakai (Dang Gui) root as a novel anti-androgen/AR agent has been highlighted and the mechanisms to account for the specific anti-AR actions have been identified: rapid block of AR nuclear translocation, inhibition of binding of 5-dihydrotestesterone to AR, and increased proteasomal degradation of AR protein. Structure-activity analyzes reveal a critical requirement of the side-chain on decursin or its structural isomer decursinol angelate for anti-AR, cell-cycle arrest and pro-apoptotic activities.

This work demonstrates the feasibility of using activity-guided fractionation in cell culture assays combined with mechanistic studies to identify novel anti-androgen/AR agents from complex herbal mixtures (Lu et al., 2007).

MDR

Combination cancer therapy is one of the attractive approaches to overcome drug resistance of cancer cells. In the present study, Jang et al (2013) investigated the synergistic effect of decursin from Angelica gigas and doxorubicin on the induction of apoptosis in three human multiple myeloma cells. The combined treatment reduced mitochondrial membrane potential., suppressed the phosphorylation of JAK2, STAT3, and Src, activated SHP-2, and attenuated the expression of cyclind-D1 and survivin in U266 cells.

Overall, the combination treatment of decursin and doxorubicin can enhance apoptotic activity via mTOR and/or STAT3 signaling pathway in multiple myeloma cells.

Breast Cancer

Decursin significantly reduced protein expression and enzymatic activity of Pin1 in MDA-MB-231 cells. Kim et al (2013) found that decursin treatment enhanced the p53 expression level and failed to down-regulate Pin1 in the cells transfected with p53 siRNA, indicating the importance of p53 in the decursin-mediated Pin1 inhibition in MDA-MB-231 cells. Decursin stimulated association between peptidyl-prolyl cis/trans isomerase Pin1 to p53. Moreover, decursin facilitated p53 transcription in MDA-MB-231 cells. Overall, the study suggests the potential of decursin as an attractive cancer therapeutic agent for breast cancer by targeting Pin1.

References

Jang J, Jeong SJ, Kwon HY, Jung JH, et al. (2013). Decursin and Doxorubicin Are in Synergy for the Induction of Apoptosis via STAT3 and/or mTOR Pathways in Human Multiple Myeloma Cells. Evid Based Complement Alternat Med. 2013:506324. doi: 10.1155/2013/506324.

Kim JH, Jung JH, Kim SH, Jeong SJ. (2013). Decursin Exerts Anti-cancer Activity in MDA-MB-231 Breast Cancer Cells Via Inhibition of the Pin1 Activity and Enhancement of the Pin1/p53 Association.Phytother Res. doi: 10.1002/ptr.4986.

Lee S, Lee YS, Jung SH, et al. (2003). Anti-tumor activities of decursinol angelate and decursin from Angelica gigas. Arch Pharm Res, 26(9):727-30.

Lee SH, Lee JH, Kim EJ, et al. (2012). A novel derivative of decursin, CSL-32, blocks migration and production of inflammatory mediators and modulates PI3K and NF- κB activities in HT1080 cells. Cell Biol Int, 36(7):683-8. doi: 10.1042/CBI20110257.

Lu JX, Kim SH, Jiang C, Lee JJ, Guo JM. (2007). Oriental herbs as a source of novel anti-androgen and prostate cancer chemo-preventive agents. Acta Pharmacologica Sinica, 28, 1365–1372. doi:10.1111/j.1745-7254.2007.00683.x

Mahat B, Chae JW, Baek IH, et al. (2012). Physicochemical characterization and toxicity of decursin and their derivatives from Angelica gigas. Biol Pharm Bull, 35(7):1084-90.

180, Angelica gigas, Angelica gigas (Nakai), angiogenesis, Anti-cancer, anti-tumor, apoptosis, Apoptotic, AR, Breast cancer, cell-cycle arrest, Chapter 7 Isolates and Cancer Research, Chemoprevention, Chemotherapy, Fibrosarcoma, HT1080, IL-8, inflammation, JAK2, MDR, MTOR, p53, Pro-apoptotic, Prostate cancer, Sarcoma, STAT3, TNF

Decursin

Cancer: Prostate, breast, fibrosarcoma, sarcoma

Action: MDR, inflammation, anti-cancer, angiogenesis

Decursin is isolated from Angelica gigas (Nakai).

Angelica gigas NAKAI is used to treat dysmenorrhea, amenorrhea, menopause, abdominal pain, injuries, migraine, and arthritis. The physicochemical and toxicological characterization of compounds in A. gigas NAKAI, decursin, decursinol angelate, diketone decursin, ether decursin, epoxide decursin and oxim decursin, have been extensively studied (Mahat et al., 2012).

Sarcoma; Anti-cancer

The in vivo anti-tumor activities of decursinol angelate (1) and decursin (2) isolated from the roots of Angelica gigas were investigated. These two compounds, when administered consecutively for 9 days at 50 and 100 mg/kg i.p. in mice, caused a significant increase in the life span and a significant decrease in the tumor weight and volume of mice inoculated with Sarcoma-180 tumor cells. These results suggest that decursinol angelate (1) and decursin (2) from A. gigas have anti-tumor activities (Lee et al., 2003).

Fibrosarcoma

Decursin and related coumarin compounds in herbal extracts have a number of biological activities against inflammation, angiogenesis and cancer. The human fibrosarcoma cell line, HT1080, was treated with TNFα (tumor necrosis factor α) in the presence or absence of CSL-32. Treatment of HT1080 cells with a derivative of decursin (CSL-32) inhibited their proliferation, without affecting cell viability, and TNF α-induced expression of pro-inflammatory mediators, such as MMP-9 (matrix metalloproteinase-9) and IL-8 (interleukin-8) (Lee et al., 2012).

Prostate Cancer

Androgen and androgen receptor (AR) signaling are crucial for the genesis of prostate cancer (PCa), which can often develop into androgen-ligand-independent diseases that are lethal to patients. As current chemotherapy is largely ineffective for PCa and has serious toxic side-effects, a collaborative effort has been initiated to identify and develop novel, safe and naturally occurring agents that target AR signaling from Oriental medicinal herbs for the chemoprevention and treatment of PCa. The discovery of decursin from an Oriental formula containing Korean Angelica gigas Nakai (Dang Gui) root as a novel anti-androgen/AR agent has been highlighted and the mechanisms to account for the specific anti-AR actions have been identified: rapid block of AR nuclear translocation, inhibition of binding of 5-dihydrotestesterone to AR, and increased proteasomal degradation of AR protein. Structure-activity analyzes reveal a critical requirement of the side-chain on decursin or its structural isomer decursinol angelate for anti-AR, cell-cycle arrest and pro-apoptotic activities.

This work demonstrates the feasibility of using activity-guided fractionation in cell culture assays combined with mechanistic studies to identify novel anti-androgen/AR agents from complex herbal mixtures (Lu et al., 2007).

MDR

Combination cancer therapy is one of the attractive approaches to overcome drug resistance of cancer cells. In the present study, Jang et al (2013) investigated the synergistic effect of decursin from Angelica gigas and doxorubicin on the induction of apoptosis in three human multiple myeloma cells. The combined treatment reduced mitochondrial membrane potential., suppressed the phosphorylation of JAK2, STAT3, and Src, activated SHP-2, and attenuated the expression of cyclind-D1 and survivin in U266 cells.

Overall, the combination treatment of decursin and doxorubicin can enhance apoptotic activity via mTOR and/or STAT3 signaling pathway in multiple myeloma cells.

Breast Cancer

Decursin significantly reduced protein expression and enzymatic activity of Pin1 in MDA-MB-231 cells. Kim et al (2013) found that decursin treatment enhanced the p53 expression level and failed to down-regulate Pin1 in the cells transfected with p53 siRNA, indicating the importance of p53 in the decursin-mediated Pin1 inhibition in MDA-MB-231 cells. Decursin stimulated association between peptidyl-prolyl cis/trans isomerase Pin1 to p53. Moreover, decursin facilitated p53 transcription in MDA-MB-231 cells. Overall, the study suggests the potential of decursin as an attractive cancer therapeutic agent for breast cancer by targeting Pin1.

References

Jang J, Jeong SJ, Kwon HY, Jung JH, et al. (2013). Decursin and Doxorubicin Are in Synergy for the Induction of Apoptosis via STAT3 and/or mTOR Pathways in Human Multiple Myeloma Cells. Evid Based Complement Alternat Med. 2013:506324. doi: 10.1155/2013/506324.

Kim JH, Jung JH, Kim SH, Jeong SJ. (2013). Decursin Exerts Anti-cancer Activity in MDA-MB-231 Breast Cancer Cells Via Inhibition of the Pin1 Activity and Enhancement of the Pin1/p53 Association.Phytother Res. doi: 10.1002/ptr.4986.

Lee S, Lee YS, Jung SH, et al. (2003). Anti-tumor activities of decursinol angelate and decursin from Angelica gigas. Arch Pharm Res, 26(9):727-30.

Lee SH, Lee JH, Kim EJ, et al. (2012). A novel derivative of decursin, CSL-32, blocks migration and production of inflammatory mediators and modulates PI3K and NF- κB activities in HT1080 cells. Cell Biol Int, 36(7):683-8. doi: 10.1042/CBI20110257.

Lu JX, Kim SH, Jiang C, Lee JJ, Guo JM. (2007). Oriental herbs as a source of novel anti-androgen and prostate cancer chemo-preventive agents. Acta Pharmacologica Sinica, 28, 1365–1372. doi:10.1111/j.1745-7254.2007.00683.x

Mahat B, Chae JW, Baek IH, et al. (2012). Physicochemical characterization and toxicity of decursin and their derivatives from Angelica gigas. Biol Pharm Bull, 35(7):1084-90.

Akt, anti-apoptotic, Anti-cancer, anti-inflammatory, anti-proliferative, anti-tumor, apoptosis, Apoptotic, Bcl-2, Breast cancer, cell-cycle arrest, Chapter 7 Isolates and Cancer Research, Chemotherapy, Colon Cancer or Colorectal cancer, cytotoxic, epidermal growth factor receptor, G2/M, growth-inhibitory, HepG2, HER-2, HER-2/neu, HER2, HIF, HL-60, HL-60/ADR, induces apoptosis, Induces cytotoxicity, inflammation, JAK2, LS1034, Lung cancer, Mahlavu, PLC/PRF/5 and HepG2, Mcl-1, MDA-MB-231, MDR, MDR-1, MDR-1, MTOR, P-gp, p21, p53, Pancreatic cancer, ROS, S, STAT3

Emodin (See also Aloe-Emodin)

Cancer:
Breast, colon, liver, chemotherapy, myeloma, oral., pancreatic, hepatocellular carcinoma, lung, leukemia

Action: MDR-1, cell-cycle arrest

Emodin is an active natural anthraquinone derivative component of a traditional Chinese and Japanese medicine isolated from the root and rhizomes of Rheum palmatum L., Senna obtusifolia [(L.) H.S.Irwin & Barneby], Fallopia japonica [Houtt. (Ronse Decr.)], Kalimeris indica (L.) Sch.Bip., Ventilago madraspatana (Gaertn.), Rumex nepalensis (Spreng.), Fallopia multiflora [(Thunb.) Haraldson], Cassia occidentalis [(L.) Link], Senna siamea [(Lam.) Irwin et Barneby] and Acalypha australis (L.).

Aloe-emodin is an active natural anthraquinone derivative, and is found in the roots and rhizomes of numerous Chinese medicinal herbs (including Rheum palmatum L) and exhibits anti-cancer effects on many types of human cancer cell lines.

Administration of rhubarb (Emodin) can effectively reverse severe acute pancreatitis (SAP) by regulating the levels of IL-15 and IL-18 (Yu & Yang, 2013).

Pancreatic Cancer

Emodin is a tyrosine kinase inhibitor that has an inhibitory effect on mammalian cell-cycle modulation in specific oncogene-overexpressing cells. Recently, there has been great progress in the preclinical study of the anti-cancer mechanisms of emodin. A recent study revealed that emodin has therapeutic effects on pancreatic cancer through various anti-tumor mechanisms. Notably, the therapeutic efficacy of emodin in combination with chemotherapy was found to be higher than the comparable single chemotherapeutic regime, and the combination therapy also exhibited fewer side-effects (Wei et al., 2013).

Hepatocellular Carcinoma, Pancreatic, Breast, Colorectal and Lung Cancers, and Leukemia

Emodin is found as an active ingredient in different Chinese herbs including Rheum palmatum and Polygonam multiflorum, and has diuretic, vasorelaxant, anti-bacterial., anti-viral., anti-ulcerogenic, anti-inflammatory, and anti-cancer effects. The anti-inflammatory effects of emodin have been exhibited in various in vitro as well as in vivo models of inflammation including pancreatitis, arthritis, asthma, atherosclerosis and glomerulonephritis. As an anti-cancer agent, emodin has been shown to suppress the growth of various tumor cell lines including hepatocellular carcinoma, pancreatic, breast, colorectal., leukemia, and lung cancers. Emodin is a pleiotropic molecule capable of interacting with several major molecular targets including NF-κB, casein kinase II, HER2/neu, HIF-1α, AKT/mTOR, STAT3, CXCR4, topoisomerase II, p53, p21, and androgen receptors which are involved in inflammation and cancer (Shrimali et al., 2013).

Hepatocellular Carcinoma

It has been found that emodin induces apoptotic responses in the human hepatocellular carcinoma cell lines (HCC) Mahlavu, PLC/PRF/5 and HepG2. The addition of emodin to these three cell lines led to inhibition of growth in a time-and dose-dependent manner. Emodin generated reactive oxygen species (ROS) in these cells which brought about a reduction of the intracellular mitochondrial transmembrane potential (ΔΨ m), followed by the activation of caspase–9 and caspase–3, leading to DNA fragmentation and apoptosis.

Preincubation of hepatoma cell lines with the hydrogen peroxide-scavenging enzyme, catalase (CAT) and cyclosporin A (CsA), partially inhibited apoptosis. These results demonstrate that enhancement of generation of ROS, DeltaPsim disruption and caspase activation may be involved in the apoptotic pathway induced by emodin (Jing et al., 2002).

Colon Cancer

In in vitro study, emodin induced cell morphological changes, decreased the percentage of viability, induced G2/M phase arrest and increased ROS and Ca(2+) productions as well as loss of mitochondrial membrane potential (ΔΨ(m)) in LS1034 cells. Emodin-triggered apoptosis was also confirmed by DAPI staining and these effects are concentration-dependent.

In in vivo study, emodin effectively suppressed tumor growth in tumor nude mice xenografts bearing LS1034. Overall, the potent in vitro and in vivo anti-tumor activities of emodin suggest that it might be developed for treatment of colon cancer in the future (Ma et al., 2012).

Myeloid Leukemia

It has been shown that emodin significantly induces cytotoxicity in the human myeloma cells through the elimination of myeloid cell leukemia 1 (Mcl-1). Emodin inhibited interleukin-6–induced activation of Janus-activated kinase 2 (JAK2) and phosphorylation of signal transducer and activator of transcription 3 (STAT3), followed by the decreased expression of Mcl-1. Activation of caspase-3 and caspase-9 was triggered by emodin, but the expression of other anti-apoptotic Bcl-2 family members, except Mcl-1, did not change in the presence of emodin. To clarify the importance of Mcl-1 in emodin-induced apoptosis, the Mcl-1 expression vector was introduced into the human myeloma cells by electroporation. Induction of apoptosis by emodin was almost abrogated in Mcl-1–overexpressing myeloma cells as the same level as in parental cells, which were not treated with emodin. Emodin therefore inhibits interleukin-6–induced JAK2/STAT3 pathway selectively and induces apoptosis in myeloma cells via down-regulation of Mcl-1, which is a good target for treating myeloma. Taken together, these results show emodin as a new potent anti-cancer agent for the treatment of multiple myeloma patients (Muto et al., 2007).

Breast Cancer; Block HER-2

The mechanism by which emodin prevents breast cancer is unknown; however the product of the HER-2/neu proto-oncogene, HER2 has been proposed to be involved. The product of the HER-2/neu proto-oncogene, HER2, is the second member of the human epidermal growth factor receptor (HER) family of tyrosine kinase receptors and has been suggested to be a ligand orphan receptor. Amplification of the HER2 gene and overexpression of the HER2 protein induces cell transformation and has been demonstrated in 10% to 40% of human breast cancer. HER2 overexpression has been suggested to associate with tumor aggressiveness, prognosis and responsiveness to hormonal and cytotoxic agents in breast cancer patients. These findings indicate that HER2 is an appropriate target for tumor-specific therapies.

A number of approaches have been investigated: (1) a humanized monoclonal antibody against HER2, rhuMAbHER2 (trastuzumab), which is already approved for clinical use in the treatment of patients with metastatic breast cancer; (2) tyrosine kinase inhibitors, such as emodin, which block HER2 phosphorylation and its intracellullar signaling; (3) active immunotherapy, such as vaccination; and (4) heat shock protein (Hsp) 90-associated signal inhibitors, such as radicicol derivatives, which induce degradation of tyrosine kinase receptors, such as HER2 (Kurebayashi, 2001).

MDR

The effects of emodin on the nucleoside transport and multi-drug resistance in cancer cells has also been investigated. Nucleoside transport inhibition was determined by thymidine incorporation assay. The cytotoxicity to cancer cells was determined by MTT assay. The pump efflux activity and the expression of P glycoprotein were examined by flow cytometric assay. Emodin was active in the inhibition of nucleoside transport, with an IC 50 value of 9 9 µmol·L -1. Emodin markedly enhanced the cytotoxicity of 5 FU, MMC and MTX against human hepatoma BEL 7402 cells and partly reversed the multi-drug resistance in human breast cancer MCF 7/Adr cells.

Emodin inhibited P-gp pump efflux activity and reduced the expression of P gp in MCF 7/Adr cells. These findings provide a biological basis for the application of emodin as a biochemical modulator to potentiate the effects of anti-tumor drugs and reverse the multi-drug resistance in cancer cells (Jiang et al., 2009).

Cell-cycle Arrest

Large quantities of emodin were isolated from the roots of Rheum emodi and a library of novel emodin derivatives 2–15 were prepared to evaluate their anti-proliferative activities against HepG2, MDA-MB-231 and NIH/3T3 cells lines. The derivatives 3 and 12 strongly inhibited the proliferation of HepG2 and MDA-MB-231 cancer cell line with an IC50 of 5.6, 13.03 and 10.44, 5.027, respectively, which is comparable to marketed drug epirubicin (III). The compounds 3 and 12 were also capable of inducing cell-cycle arrest and caspase dependent apoptosis in HepG2 cell lines and exhibit DNA intercalating activity. These emodin derivatives hold promise for developing safer alternatives to the marketed epirubicin (Narender et al., 2013).

Cell-cycle Arrest; MDR1 & AZT

3'-azido-3'-deoxythymidine (AZT) and emodin altered the cell-cycle distribution and led to an accumulation of cells in S phase. Meanwhile, the expression of MDR1 mRNA/p-gp protein was markedly decreased. These results show a synergistic growth-inhibitory effect of AZT and emodin in K562/ADM cells, which is achieved through S phase arrest. MDR1 might ultimately be responsible for these phenomena (Chen et al., 2013).

References

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