Category Archives: PI3K/Akt

A549, Akt, angiogenesis, Anti-angiogenic, Anti-cancer, Anti-estrogenic, anti-inflammatory, anti-lymphangiogenesis, anti-metastasis, Anti-metastatic, anti-tumor, anti-tumor activity, apoptosis, apoptosis-inducing, Apoptotic, BAX, Bcl-2, Breast cancer, c-ErbB2, CAM, CD31, cell-cycle arrest, Cervical cancer, Chapter 7 Isolates and Cancer Research, chemo-preventive, Chemo-preventive agent, Chemo-protective, Chemo-sensitizer, Chemotherapy, Colon Cancer or Colorectal cancer, COX-2, ER, ER-negative, ER-positive, ERK1, G1, GBC-SD, HCT116, HeLa, Hep G2,Hep 3B and SK-Hep1, HIF, HT-29, hypoxia-induced drug resistance, IGF-1, IL-1, iNOS, LM8, Lung cancer, MCF-7, MCP-1, MDR, metastasis, Multi-Drug Resistance, Multi-drug resistance, neuro-protective, Osteosarcoma, p-Akt, p27, p53, PARP, PGE2, PI3K, PI3K/Akt, Pro-apoptotic, pro-oxidative, ROS, Sarcoma, T47D, MDA-MB-231, TNF, TRAIL, VEGF, VEGF, VEGFR

Wogonin

April 21, 2014 brian

Cancer:
Breast, lung (NSCLC), gallbladder carcinoma, osteosarcoma, colon, cervical

Action: Neuro-protective, anti-lymphangiogenesis, anti-angiogenic, anti-estrogenic, chemo-sensitizer, pro-oxidative, hypoxia-induced drug resistance, anti-metastatic, anti-tumor, anti-inflammatory

Wogonin is a plant monoflavonoid isolated from Scutellaria rivularis (Benth.) and Scutellaria baicalensis (Georgi).

Breast Cancer; ER+ & ER-

Effects of wogonin were examined in estrogen receptor (ER)-positive and -negative human breast cancer cells in culture for proliferation, cell-cycle progression, and apoptosis. Cell growth was attenuated by wogonin (50-200 microM), independently of its ER status, in a time- and concentration-dependent manner. Apoptosis was enhanced and accompanied by up-regulation of PARP and Caspase 3 cleavages as well as pro-apoptotic Bax protein. Akt activity was suppressed and reduced phosphorylation of its substrates, GSK-3beta and p27, was observed. Suppression of Cyclin D1 expression suggested the down-regulation of the Akt-mediated canonical Wnt signaling pathway.

ER expression was down-regulated in ER-positive cells, while c-ErbB2 expression and its activity were suppressed in ER-negative SK-BR-3 cells. Wogonin feeding to mice showed inhibition of tumor growth of T47D and MDA-MB-231 xenografts by up to 88% without any toxicity after 4 weeks of treatment. As wogonin was effective both in vitro and in vivo, our novel findings open the possibility of wogonin as an effective therapeutic and/or chemo-preventive agent against both ER-positive and -negative breast cancers, particularly against the more aggressive and hormonal therapy-resistant ER-negative types (Chung et al., 2008).

Neurotransmitter Action

Kim et al. (2011) found that baicalein and wogonin activated the TREK-2 current by increasing the opening frequency (channel activity: from 0.05 ± 0.01 to 0.17 ± 0.06 in baicalein treatment and from 0.03 ± 0.01 to 0.29 ± 0.09 in wogonin treatment), while leaving the single-channel conductance and mean open time unchanged. Baicalein continuously activated TREK-2, whereas wogonin transiently activated TREK-2. Application of baicalein and wogonin activated TREK-2 in both cell attached and excised patches, suggesting that baicalein and wogonin may modulate TREK-2 either directly or indirectly with different mechanisms. These results suggest that baicalein- and wogonin-induced TREK-2 activation help set the resting membrane potential of cells exposed to pathological conditions and thus may give beneficial effects in neuroprotection.

Anti-metastasic

The migration and invasion assay was used to evaluate the anti-metastasis effect of wogonin. Wogonin at the dose of 1–10 µM, which did not induce apoptosis, significantly inhibited the mobility and invasion activity of human gallbladder carcinoma GBC-SD cells. In addition, the expressions of matrix metalloproteinase (MMP)-2, MMP-9 and phosphorylated extracellular regulated protein kinase 1/2 (ERK1/2) but not phosphorylated Akt were dramatically suppressed by wogonin in a concentration-dependent manner. Furthermore, the metastasis suppressor maspin was confirmed as the downstream target of wogonin.

These findings suggest that wogonin inhibits cell mobility and invasion by up-regulating the metastasis suppressor maspin. Together, these data provide novel insights into the chemo-protective effect of wogonin, a main active ingredient of Chinese medicine Scutellaria baicalensis (Dong et al., 2011).

Anti-tumor and Anti-metastatic

Kimura & Sumiyoshi (2012) examined the effects of wogonin isolated from Scutellaria baicalensis roots on tumor growth and metastasis using a highly metastatic model in osteosarcoma LM8-bearing mice. Wogonin (25 and 50mg/kg, twice daily) reduced tumor growth and metastasis to the lung, liver and kidney, angiogenesis (CD31-positive cells), lymphangiogenesis (LYVE-1-positive cells), and TAM (F4/80-positive cell) numbers in the tumors of LM8-bearing mice. Wogonin (10–100µM) also inhibited increases in IL-1β production and cyclooxygenase (COX)-2 expression induced by lipopolysaccharide in THP-1 macrophages. The anti-tumor and anti-metastatic actions of wogonin may be associated with the inhibition of VEGF-C-induced lymphangiogenesis through a reduction in VEGF-C-induced VEGFR-3 phosphorylation by the inhibition of COX-2 expression and IL-1β production in Tumor-associated macrophages (TAMs).

Anti-inflammatory

Wogonin extracted from Scutellariae baicalensis and S. barbata is a cell-permeable and orally available flavonoid that displays anti-inflammatory properties. Wogonin is reported to suppress the release of NO by iNOS, PGE2 by COX-2, pro-inflammatory cytokines, and MCP-1 gene expression and NF-kB activation (Chen et al., 2008).

Hypoxia-Induced Drug Resistance (MDR)

Hypoxia-induced drug resistance is a major obstacle in the development of effective cancer therapy. The reversal abilities of wogonin on hypoxia resistance were examined and the underlying mechanisms discovered. MTT assay revealed that hypoxia increased maximal 1.71-, 2.08-, and 2.15-fold of IC50 toward paclitaxel, ADM, and DDP in human colon cancer cell lines HCT116, respectively. Furthermore, wogonin showed strong reversal potency in HCT116 cells in hypoxia and the RF reached 2.05. Hypoxia-inducible factor-1α (HIF-1α) can activate the expression of target genes involved in glycolysis. Wogonin decreased the expression of glycolysis-related proteins (HKII, PDHK1, LDHA), glucose uptake, and lactate generation in a dose-dependent manner.

In summary, wogonin could be a good candidate for the development of a new multi-drug resistance (MDR) reversal agent and its reversal mechanism probably is due to the suppression of HIF-1α expression via inhibiting PI3K/Akt signaling pathway (Wang et al., 2013).

NSCLC

Wogonin, a flavonoid originated from Scutellaria baicalensis Georgi, has been shown to enhance TRAIL-induced apoptosis in malignant cells in in vitro studies. In this study, the effect of a combination of TRAIL and wogonin was tested in a non-small-cell lung cancer xenografted tumor model in nude mice. Consistent with the in vitro study showing that wogonin sensitized A549 cells to TRAIL-induced apoptosis, wogonin greatly enhanced TRAIL-induced suppression of tumor growth, accompanied with increased apoptosis in tumor tissues as determined by TUNEL assay.

The down-regulation of these antiapoptotic proteins was likely mediated by proteasomal degradation that involved intracellular reactive oxygen species (ROS), because wogonin robustly induced ROS accumulation and ROS scavengers butylated hydroxyanisole (BHA) and N-acetyl-L-cysteine (NAC) and the proteasome inhibitor MG132 restored the expression of these antiapoptotic proteins in cells co-treated with wogonin and TRAIL.

These results show for the first time that wogonin enhances TRAIL's anti-tumor activity in vivo, suggesting this strategy has an application potential for clinical anti-cancer therapy (Yang et al., 2013).

Colon Cancer

Following treatment with baicalein or wogonin, several apoptotic events were observed, including DNA fragmentation, chromatin condensation and increased cell-cycle arrest in the G1 phase. Baicalein and wogonin decreased Bcl-2 expression, whereas the expression of Bax was increased in a dose-dependent manner compared with the control. Furthermore, the induction of apoptosis was accompanied by an inactivation of phosphatidylinositol 3-kinase (PI3K)/Akt in a dose-dependent manner.

The administration of baicalein to mice resulted in the inhibition of the growth of HT-29 xenografts without any toxicity following 5 weeks of treatment. The results indicated that baicalein induced apoptosis via Akt activation in a p53-dependent manner in the HT-29 colon cancer cells and that it may serve as a chemo-preventive or therapeutic agent for HT-29 colon cancer (Kim et al., 2012).

Breast

The involvement of insulin-like growth factor-1 (IGF-1) and estrogen receptor α (ERα) in the inhibitory effect of wogonin on the breast adenocarcinoma growth was determined. Moreover, the effect of wogonin on the angiogenesis of chick chorioallantoic membrane (CAM) was also investigated. The results showed wogonin and ICI182780 both exhibited a potent ability to blunt IGF-1-stimulated MCF-7 cell growth. Either of wogonin and ICI182780 significantly inhibited ERα and p-Akt expressions in IGF-1-treated cells. The inhibitory effect of wogonin showed no difference from that of ICI182780 on IGF-1-stimulated expressions of ERα and p-Akt. Meanwhile, wogonin at different concentrations showed significant inhibitory effect on CAM angiogenesis.

These results suggest the inhibitory effect of wogonin on breast adenocarcinoma growth via inhibiting IGF-1-mediated PI3K-Akt pathway and regulating ERα expression. Furthermore, wogonin has a strong anti-angiogenic effect on CAM model (Ma et al., 2012).

Chemoresistance; Cervical Cancer, NSCLC

Chemoresistance to cisplatin is a major limitation of cisplatin-based chemotherapy in the clinic. The combination of cisplatin with other agents has been recognized as a promising strategy to overcome cisplatin resistance. Previous studies have shown that wogonin (5,7-dihydroxy-8-methoxyflavone), a flavonoid isolated from the root of the medicinal herb Scutellaria baicalensis Georgi, sensitizes cancer cells to chemotheraputics such as etoposide, adriamycin, tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and TNF.

In this study, the non-small-cell lung cancer cell line A549 and the cervical cancer cell line HeLa were treated with wogonin or cisplatin individually or in combination. It was found for the first time that wogonin is able to sensitize cisplatin-induced apoptosis in both A549 cells and HeLa cells as indicated by the potentiation of activation of caspase-3, and cleavage of the caspase-3 substrate PARP in wogonin and cisplatin co-treated cells.

Results provided important new evidence supporting the potential use of wogonin as a cisplatin sensitizer for cancer therapy (He et al., 2012).

References

Chen LG, Hung LY, Tsai KW, et al. (2008). Wogonin, a bioactive flavonoid in herbal tea, inhibits inflammatory cyclooxygenase-2 gene expression in human lung epithelial cancer cells. Mol Nutr Food Res. 52:1349-1357.

Chung H, Jung YM, Shin DH, et al. (2008). Anti-cancer effects of wogonin in both estrogen receptor-positive and -negative human breast cancer cell lines in vitro and in nude mice xenografts. Int J Cancer, 122(4):816-22.

Dong P, Zhang Y, Gu J, et al. (2011). Wogonin, an active ingredient of Chinese herb medicine Scutellaria baicalensis, inhibits the mobility and invasion of human gallbladder carcinoma GBC-SD cells by inducing the expression of maspin. J Ethnopharmacol, 137(3):1373-80. doi: 10.1016/j.jep.2011.08.005.

He F, Wang Q, Zheng XL, et al. (2012). Wogonin potentiates cisplatin-induced cancer cell apoptosis through accumulation of intracellular reactive oxygen species. Oncology Reports, 28(2), 601-605. doi: 10.3892/or.2012.1841.

Kim EJ, Kang D, Han J. (2011). Baicalein and wogonin are activators of rat TREK-2 two-pore domain K+ channel. Acta Physiologica, 202(2):185–192. doi: 10.1111/j.1748-1716.2011.02263.x.

Kim SJ, Kim HJ, Kim HR, et al. (2012). Anti-tumor actions of baicalein and wogonin in HT-29 human colorectal cancer cells. Mol Med Rep, 6(6):1443-9. doi: 10.3892/mmr.2012.1085.

Kimura Y & Sumiyoshi M. (2012). Anti-tumor and anti-metastatic actions of wogonin isolated from Scutellaria baicalensis roots through anti-lymphangiogenesis. Phytomedicine, 20(3-4):328-336. doi:10.1016/j.phymed.2012.10.016

Ma X, Xie KP, Shang F, et al. (2012). Wogonin inhibits IGF-1-stimulated cell growth and estrogen receptor α expression in breast adenocarcinoma cell and angiogenesis of chick chorioallantoic membrane. Sheng Li Xue Bao, 64(2):207-12.

Wang H, Zhao L, Zhu LT, et al. (2013). Wogonin reverses hypoxia resistance of human colon cancer HCT116 cells via down-regulation of HIF-1α and glycolysis, by inhibiting PI3K/Akt signaling pathway. Mol Carcinog. doi: 10.1002/mc.22052.

Yang L, Wang Q, Li D, et al. (2013). Wogonin enhances anti-tumor activity of tumor necrosis factor-related apoptosis-inducing ligand in vivo through ROS-mediated down-regulation of cFLIPL and IAP proteins. Apoptosis, 18(5):618-26. doi: 10.1007/s10495-013-0808-8.

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

April 21, 2014 brian

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

April 20, 2014 brian

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.

Akt, Anti-cancer, anti-tumor, apoptosis, Apoptotic, cell-cycle arrest, Chapter 7 Isolates and Cancer Research, chemo-preventive, Chemo-preventive agent, CHK2, Colon Cancer or Colorectal cancer, ER, ER-positive, G0/G1, G1, HER-2, HER-2/neu, Ovarian cancer, PARP, PI3K, PI3K/Akt

Antrodia camphorata

April 18, 2014 brian

Cancer: Leukemia, colorectal., ER+ ovarian cancer

Action: Anti-cancer

Antrodia Camphorata [(M. Zang & C.H. Su) Sheng H. Wu, Ryvarden & T.T.] is a native Taiwanese mushroom which is used in Asian folk medicine. It is also known as Ganoderma camphoratum (M. Zang & C.H. Su) and Taiwanofungus camphoratus [(M. Zang & C.H. Su) Sheng H. Wu, Z.H. Yu, Y.C. Dai & C.H. Su].

Anti-tumor

Mycotherapy is defined as the study of the use of extracts and compounds obtained from mushrooms as medicines or health-promoting agents. An increasing number of studies in the past few years have revealed mushroom extracts as potent anti-tumor agents. Also, numerous studies have been conducted on bioactive compounds isolated from mushrooms reporting the heteropolysaccharides, β-glucans, α-glucans, proteins, complexes of polysaccharides with proteins, fatty acids, nucleoside antagonists, terpenoids, sesquiterpenes, lanostanoids, sterols and phenolic acids, as promising anti-tumor agents (Popović et al., 2013).

Leukemia

Antrodia camphorata (AC) is a native Taiwanese mushroom, which is used in Asian folk medicine as a chemo-preventive agent. The triterpenoid-rich fraction (FEA) was obtained from the ethanolic extract of AC and characterized by high performance liquid chromatography (HPLC). FEA caused DNA damage in leukemia HL60 cells which was characterized by phosphorylation of H2A.X and Chk2. It also exhibited apoptotic effect which was correlated to the enhancement of PARP cleavage and to the activation of caspase 3.

Taken together, these results provide the first evidence that pure AC component inhibits tumor growth in an in vivo model, thereby backing the traditional anti-cancer use of AC in Asian countries (Du et al., 2012).

Colon Cancer

Antrodia camphorata (AC) grown on germinated brown rice (CBR) was studied in HT-29 human colon cancer cells. CBR 80% ethanol EtOAc fraction showed the strongest inhibitory activity against HT-29 cell proliferation. Induction of G0/G1 cell-cycle arrest on human colon carcinoma cell was observed in CBR EtOAc fraction-treated cells. We found that CBR decreased the level of proteins involved in G0/G1 cell-cycle arrest and apoptosis. CBR EtOAc fraction inhibited the β-catenin signaling pathway, supporting its suppressive activity on the level of cyclin D1 (Park, Lim, & Park, 2013).

A new enynyl-benzenoid, antrocamphin O (1,4,7-dimethoxy-5-methyl-6-(3'-methylbut-3-en-1-ynyl)benzo[d][1,3]dioxide), and the known benzenoids antrocamphin A and 7-dimethoxy-5-methyl-1,3-benzodioxole, were isolated from the fruiting bodies of Antrodia camphorata (Taiwanofungus camphoratus). The benzenoids were tested successfully for cytotoxicity against the HT29, HTC15, DLD-1, and COLO 205 colon cancer cell lines (Chen et al., 2013).

ER+ Ovarian Cancer

MTT and colony formation assays showed that Antrodia camphorata (AC) induced a dose-dependent reduction in SKOV-3 cell growth. Immunoblot analysis demonstrated that HER-2/neu activity and tyrosine phosphorylation were significantly inhibited by AC. Furthermore, AC treatment significantly inhibited the activation of PI3K/Akt and their downstream effector β-catenin (Yang et al., 2013).

References

Chen PY, Wu JD, Tang KY, et al. (2013). Isolation and synthesis of a bioactive benzenoid derivative from the fruiting bodies of Antrodia camphorata. Molecules, 18(7):7600-8. doi: 10.3390/molecules18077600.

Du YC, Chang FR, Wu TY, et al. (2012). Anti-leukemia component, dehydroeburicoic acid from Antrodia camphorata induces DNA damage and apoptosis in vitro and in vivo models. Phytomedicine. doi:10.1016/j.phymed.2012.03.014

Park DK, Lim YH, Park HJ. (2013). Antrodia camphorata Grown on Germinated Brown Rice Inhibits HT-29 Human Colon Carcinoma Proliferation Through Inducing G0/G1 Phase Arrest and Apoptosis by Targeting the β -Catenin Signaling. J Med Food, 16(8):681-91. doi: 10.1089/jmf.2012.2605.

Popovi ć V, Zivkovi ć J, Davidovi ć S, et al. (2013). Mycotherapy Of Cancer: An Update On Cytotoxic And Anti-tumor Activities Of Mushrooms, Bioactive Principles And Molecular Mechanisms Of Their Action. Curr Top Med Chem.

Yang HL, Lin KY, Juan YC, et al. (2013). The anti-cancer activity of Antrodia camphorata against human ovarian carcinoma (SKOV-3) cells via modulation of HER-2/neu signaling pathway. J Ethnopharmacol, 148(1):254-65. doi: 10.1016/j.jep.2013.04.023.

Akt, anti-apoptotic, Anti-cancer, anti-proliferative, apoptosis, apoptosis-inducing, Apoptotic, Aurantti Fructus Immaturus, Bcl-2, Bcl-xL, Chapter 7 Isolates and Cancer Research, ER, ER-positive, FasL, induces apoptosis, Mcl-1, Neuroblastoma, PI3K, PI3K/Akt, SH-SY5Y

Angelicin

April 18, 2014 brian

Cancer: Leukemia, colon, ER+ Ovarian

Action: Apoptotic, anti-cancer

Angelicin is a furanocoumarin. It can be found in Bituminaria bituminosa and is structurally related to psoralens, a well-known chemical class of photosensitizers used for its anti-proliferative activity in treatment of different skin diseases.

Induces Apoptosis

The cellular cytotoxicity of angelicin was examined by cell viability assay, DNA fragmentation by DNA ladder assay, and activation of caspases and Bcl-2 family proteins by Western blot analyzes. The results suggest that angelicin increased cellular cytotoxicity in a dose- and time-dependent manner with IC(50) of 49.56 µM at 48 hours of incubation.

In addition, angelicin dose-dependently downregulated the expression of anti-apoptotic proteins including Bcl-2, Bcl-xL, and Mcl-1 suggesting the involvement of the intrinsic mitochondria-mediated apoptotic pathway which did not participate in Fas/FasL-induced caspase-8-mediated extrinsic, MAP kinases, and PI3K/AKT/GSK-3β pathway.

Taken together, these data indicate that angelicin is an effective apoptosis-inducing natural compound of human SH-SY5Y neuroblastoma cells which suggests that this compound may have a role in future therapies for human neuroblastoma cancer (Rahman et al., 2012).

Anti-cancer

Three crude drugs Saussureae Radix, Psoraleae Semen and Aurantti Fructus Immaturus significantly inhibited the proliferation of temperature-sensitive rat lymphatic endothelial (TR-LE) cells in vitro. Angelicin isolated from Aurantti Fructus Immaturus showed selective inhibition of the proliferation of TR-LE cells (Jeong et al., 2013). Angelicin, isolated from Bituminaria morisiana was subjected to cytotoxicity screening against a panel of human cancer cells (Leonti et al., 2010).

References

Jeong D, Watari K, Shirouzu T, et al. (2013). Studies on lymphangiogenesis inhibitors from Korean and Japanese crude drugs. Biol Pharm Bull, 36(1):152-7.

Leonti M, Casu L, Gertsch J, et al. (2010). A pterocarpan from the seeds of Bituminaria morisiana. J Nat Med. 64(3):354-7. doi: 10.1007/s11418-010-0408-7.

Rahman MA, Kim NH, Yang H, Huh SO. (2012). Angelicin induces apoptosis through intrinsic caspase-dependent pathway in human SH-SY5Y neuroblastoma cells. Mol Cell Biochem, 369(1-2):95-104. doi: 10.1007/s11010-012-1372-1.

Akt, Alismatis Rhizoma, anti-proliferative, anti-proliferative effect, apoptosis, B16F10, BAX, Bcl-2, Chapter 7 Isolates and Cancer Research, Cytostatic, cytotoxic, Gastric cancer or Stomach cancer, Hep3B, HepG2-DR, HT1080, K562-DR, Melanoma, p-Akt, PC3, PI3K, PI3K/Akt, Sarcoma, SGC7901, SKOV3

Alisol B Acetate

April 18, 2014 brian

Cancer:
Liver, melanoma, ovarian, sarcoma, gastric cancer

Action: Cytostatic, cytotoxic

Four prostane-type triterpenes were isolated from a methanol extract of Alismatis Rhizoma by bioassay-guided isolation using in vitro cytotoxic assay. The compounds were identified as alisol B 23-acetate (1), alisol C 23-acetate (2), alisol B (3), alisol A 24-acetate (4) by spectroscopic methods. Amongst the compounds, alisol B (3) showed significant cytotoxicity against SK-OV3, B16-F10, and HT1080 cancer cell lines with ED50 values of 7.5, 7.5, 4.9 microg/ml, respectively (Lee et al., 2001).

Hepatocellular Carcinoma

Long dan xie gan tang (pinyin) is one of the most commonly used herbal formulas by patients with chronic liver disease in China. Accumulated anecdotal evidence suggests that Long dan tang may have beneficial effects in patients with hepatocellular carcinoma. Long dan tang is comprised of five herbs: Gentiana root, Scutellaria root, Gardenia fruit, Alisma rhizome, and Bupleurum root. The cytotoxic effects of compounds from the five major ingredients isolated from the above plants, i.e. gentiopicroside, baicalein, geniposide, alisol B acetate and saikosaponin-d, respectively, on human hepatoma Hep3B cells, were investigated.

Results suggest that alisol B acetate and saikosaponin-d induced cell apoptosis through the caspase-3-dependent and -independent pathways, respectively. Instead of inducing apoptosis, baicalein inhibits TGF-beta(1)-induced apoptosis via increase in cellular H(2)O(2) formation and NF-kappaB activation in human hepatoma Hep3B cells (Chou, Pan, Teng & Guh, 2003).

Gastric Cancer

The cytotoxic effect of alisol B acetate on SGC7901 cells was measured by MTT assay and phase-contrast and electron microscopy. Cell-cycle and mitochondrial transmembrane potential (Deltapsim) were determined by flow cytometry and Western blotting was used to detect the expression of apoptosis-regulated gene Bcl-2, Bax, Apaf-1, caspase-3, caspase-9, Akt, P-Akt and phosphatidylinositol 3-kinases (PI3K).

Alisol B acetate inhibited the proliferation of SGC7901 cell line in a time- and dose-dependent manner. Alisol B acetate exhibits an anti-proliferative effect in SGC7901 cells by inducing apoptosis. Apoptosis of SGC7901 cells involves mitochondria-caspase and PI3K/Akt dependent pathways (Xu, Zhao & Li, 2009).

References

Chou CC, Pan SL, Teng CM, & Guh JH. (2003). Pharmacological evaluation of several major ingredients of Chinese herbal medicines in human hepatoma Hep3B cells. European Journal of Pharmaceutical Sciences, 19(5), 403-12.

Lee S, Kho Y, Min B, et al. (2001). Cytotoxic triterpenoides from Alismatis rhizome. Archives of Pharmacal Research. 24(6), 524-526.

Xu YH, Zhao LJ, & Li Y. (2009). Alisol B acetate induces apoptosis of SGC7901 cells via mitochondrial and phosphatidylinositol 3-kinases/Akt signaling pathways.

World Journal of Gastroenterology, 15(23), 2870-2877.

Akt, angiogenesis, Anti-cancer, anti-inflammatory, Anti-metastatic, anti-proliferative, apoptosis, Apoptotic, ARO, Autophagy, Autophagy inhibitor, BAX, Bcl-2, Breast cancer, Breast cancer cell lines, CDK6, cell-cycle arrest, Chapter 7 Isolates and Cancer Research, Colon Cancer or Colorectal cancer, cytotoxic, Depression or Anxiety, Down-regulates, DU145 and PC3, ER, ER-negative, Evodia rutaecarpa, G0/G1, G1, G2/M, IKK, increases intracellular ROS, inflammation, inhibits metastasis, inhibits NF-κB, Lung cancer, MCF-7 and MDA-MB-231, MDR, MTOR, Nitric Oxide, Pancreatic cancer, PI3K, PI3K/Akt, PTEN, ROS, SGC7901, TNF

Evodiamine

March 27, 2014 brian

Cancer: Pancreatic, gastric, breast; ER+, ER-, lung

Action: Inhibits NF- κB, inhibits metastasis, increases intracellular ROS, apoptosis, cell-cycle arrest, anti-cancer, MDR

Evodiamine, a naturally occurring indole alkaloid, is one of the main bioactive ingredients of Evodia rutaecarpa [(Juss.) Benth.] (alkaloidal component of the extract). With respect to the pharmacological actions of evodiamine, more attention has been paid to beneficial effects in insults involving cancer, obesity, nociception, inflammation, cardiovascular diseases, Alzheimer's disease, infectious diseases and thermo-regulative effects. Evodiamine has evolved a superior ability to bind various proteins (Yu et al., 2013). Evodiamine exhibits anti-proliferative, anti-metastatic, and apoptotic activities.

Anti-cancer, MDR

Evodiamine possesses anti-anxiety, anti-obesity, anti-nociceptive, anti-inflammatory, anti-allergic, and anti-cancer effects. As well, it has thermoregulation, protection of myocardial ischemia-reperfusion injury and vessel-relaxing activities (Kobayashi, 2003; Shin et al., 2007; Ko et al., 2007; Ji, 2011). Evodiamine exhibits anti-cancer activities both in vitro and in vivo by inducing cell-cycle arrest or apoptosis, and inhibiting angiogenesis, invasion, and metastasis in a variety of cancer cell lines (Ogasawara et al., 2001; Ogasawara et al., 2002; Fei et al., 2003; Shyu et al., 2006). It presents anti-cancer potentials at micromolar concentrations and even at the nanomolar level in some cell lines in vitro (Lee et al., 2006; Wang, Li, & Wang, 2010). Evodiamine also stimulates autophagy, which serves as a survival function (Yang et al., 2008). Compared with other compounds, evodiamine is less toxic to normal human cells, such as human peripheral blood mononuclear cells (Fei et al., 2003; Zhang et al., 2004). It also inhibits the proliferation of adriamycin-resistant human breast cancer NCI/ADR-RES cells both in vitro and in Balb-c/nude mice (Liao et al., 2005).

Lung Cancer, Cell-cycle Arrest

Evodiamine (10 mg/kg) administrated orally twice daily significantly inhibits tumor growth (Liao et al., 2005). Moreover, treatment with 10 mg/kg evodiamine from the 6th day after tumor inoculation into mice reduces lung metastasis and does not affect the body weight of mice during the experimental period (Ogasawara et al., 2001).

Cell-cycle Arrest

Evodiamine inhibits TopI enzyme, forms the DNA covalent complex with a similar concentration to that of irinotecan, and induces DNA damage (Chan et al., 2009; Tsai et al., 2010; Dong et al., 2010). However, TopI may not be the main target of this compound. Cancer cells treated with evodiamine exhibit G 2 / M phase arrest (Kan et al., 2004; Huang et al., 2004; Liao et al., 2005) rather than S phase arrest, which is not consistent with the mechanism of classic TopI inhibitors, such as irinotecan. Therefore, other targets aside from TopI may also be important for realizing the anti-cancer potentials of evodiamine. This statement is supported by the fact that evodiamine has effects on tubulin polymerization (Huang et al., 2004).

Increases Intracellular ROS, Apoptosis

Exposure to evodiamine rapidly increases intracellular ROS followed by an onset of mitochondrial depolarization (Yang et al., 2007). The generation of ROS and nitric oxide acts in synergy and triggers mitochondria-dependent apoptosis (Yang et al., 2008). Evodiamine also induces caspase-dependent and caspase-independent apoptosis, down-regulates Bcl-2 expression, and up-regulates Bax expression in some cancer cells (Zhang et al., 2003; Lee et al., 2006). The phosphatidylinositol 3-kinase/Akt/caspase and Fas ligand (Fas-L)/NF-κB signaling pathways might account for evodiamine-induced cell death. Moreover, these signals could be increased by the ubiquitin-proteasome pathway (Wang, Li, & Wang, 2010).

Inhibits Metastasis

Evodiamine has a marked inhibitory activity on tumor cell migration in vitro. When evodiamine at 10 mg/kg was administered into mice from the 6th day after tumor inoculation, the number of tumor nodules in lungs was decreased by 48% as compared to control. The inhibition rate was equivalent to that produced by cisplatin. Results suggest that evodiamine may be regarded as a promising agent in tumor metastasis therapy (Ogasawara et al., 2005).

Inhibits NF-κB

Evodiamine inhibited tumor necrosis factor (TNF)-induced Akt activation and its association with IKK. This down-regulation potentiated the apoptosis induced by cytokines and chemotherapeutic agents and suppressed TNF-induced invasive activity. Overall, these results indicate that evodiamine inhibits both constitutive and induced NF-κB activation and NF-κB-regulated gene expression (Takada et al., 2005).

Breast Cancer

Endocrine sensitivity, assessed by the expression of estrogen receptor (ER), has long been the predict factor to guide therapeutic decisions. Tamoxifen has been the most successful hormonal treatment in endocrine-sensitive breast cancer. However, in estrogen-insensitive cancer tamoxifen showed less effectiveness than in estrogen-sensitive cancer. It is interesting to develop new drugs against both hormone-sensitive and insensitive tumor. In this present study Wang et al. (2013) examined anti-cancer effects of evodiamine extracted from the Chinese herb, Evodiae fructus, in estrogen-dependent and -independent human breast cancer cells, MCF-7 and MDA-MB-231 cells, respectively.

Breast Cancer; ER+, ER-

The expression of ER α and β in protein and mRNA levels was down-regulated by evodiamine according to data from immunoblotting and RT-PCR analysis. Overall, results indicate that evodiamine mediates degradation of ER and induces caspase-dependent pathway leading to inhibition of proliferation of breast cancer cell lines. It suggests that evodiamine may in part mediate through ER-inhibitory pathway to inhibit breast cancer cell proliferation.

Evodiamine (10 mg/kg) significantly reduced tumor growth and pulmonary metastasis. In vitro, evodiamine inhibited cell migration and invasion abilities through down-regulation of MMP-9, urokinase-type plasminogen activator (uPA) and uPAR expression. Evodiamine-induced G0/G1 arrest and apoptosis were associated with a decrease in Bcl-2, cyclin D1 and cyclin-dependent kinase 6 (CDK6) expression and an increase in Bax and p27Kip1 expression (Du et al., 201).

Gastric Cancer

A study by Rasul et al. (2012) was conducted to investigate the synchronized role of autophagy and apoptosis in evodiamine-induced cytotoxic activity on SGC-7901 human gastric adenocarcinoma cells and further to elucidate the underlying molecular mechanisms. Evodiamine significantly inhibited the proliferation of SGC-7901 cells and induced G2/M phase cell-cycle arrest.

Evodiamine-induced autophagy is partially involved in the death of SGC-7901 cells which was confirmed by using the autophagy inhibitor 3-methyladenine (3-MA). Evodiamine has therapeutic potential against cancers.

Pancreatic Cancer

In vitro application of the combination therapy triggered significantly higher frequency of pancreatic cancer cells apoptosis, inhibited the activities of PI3K, Akt, PKA, mTOR and PTEN, and decreased the activation of NF-κB and expression of NF- κB-regulated products. Evodiamine can augment the therapeutic effect of gemcitabine in pancreatic cancer through direct or indirect negative regulation of the PI3K/Akt pathway (Wei et al., 2012).

References

Chan ALF, Chang WS, Chen LM et al. (2009). Evodiamine stabilizes topoisomerase I-DNA cleavable complex to inhibit topoisomerase I activity. Molecules, (14):4:1342–1352.

Dong G, Sheng C, Wang CS, et al. (2010). Selection of evodiamine as a novel topoisomerase i inhibitor by structure-based virtual screening and hit optimization of evodiamine derivatives as anti-tumor agents. Journal of Medicinal Chemistry, 53(21):7521–7531.

Du J, Wang XF, Zhou QM, et al. (2013). Evodiamine induces apoptosis and inhibits metastasis in MDA “American Typewriter”; “American Typewriter”;‑ MB-231 human breast cancer cells in vitro and in vivo. Oncol Rep, 30(2):685-94. doi: 10.3892/or.2013.2498.

Fei XF, Wang BX, T. Li TJ et al. (2003). Evodiamine, a constituent of Evodiae Fructus, induces anti-proliferating effects in tumor cells. Cancer Science, 94(1):92–98.

Huang YC, Guh JH, Teng CM. (2004). Induction of mitotic arrest and apoptosis by evodiamine in human leukemic T-lymphocytes. Life Sciences, 75(1):35–49.

Ji YB. (2011). Active Ingredients of Traditional Chinese Medicine: Pharmacology and Application. People's Medical Publishing House Co., LTD. Connecticut USA

Kan SF, Huang WJ, Lin LC, Wang PS. (2004). Inhibitory effects of evodiamine on the growth of human prostate cancer cell line LNCaP. International Journal of Cancer, 110(5):641–651.

Ko HC, Wang YH, Liou KT et al. (2007). Anti-inflammatory effects and mechanisms of the ethanol extract of Evodia rutaecarpa and its bioactive components on neutrophils and microglial cells. European Journal of Pharmacology, 555(2-3):211–217.

Kobayashi Y. (2003). The nociceptive and anti-nociceptive effects of evodiamine from fruits of Evodia rutaecarpa in mice. Planta Medica, 69(5):425–428.

Lee TJ, Kim EJ, Kim S et al. (2006). Caspase-dependent and caspase-independent apoptosis induced by evodiamine in human leukemic U937 cells. Molecular Cancer Therapeutics, 5(9):2398–2407.

Liao CH, Pan SL, Guh JH et al. (2005). Anti-tumor mechanism of evodiamine, a constituent from Chinese herb Evodiae fructus, in human multiple-drug resistant breast cancer NCI/ADR-RES cells in vitro and in vivo. Carcinogenesis, 26(5):968–975.

Ogasawara M, Matsubara T, Suzuki H. (2001). Inhibitory effects of evodiamine on in vitro invasion and experimental lung metastasis of murine colon cancer cells. Biological and Pharmaceutical Bulletin, 24(8):917–920.

Ogasawara M, Matsunaga T, Takahashi S, Saiki I, Suzuki H. (2002). Anti-invasive and metastatic activities of evodiamine. Biological and Pharmaceutical Bulletin, 25(11):1491–1493.

Rasul A, Yu B, Zhong L, et al. (2012). Cytotoxic effect of evodiamine in SGC-7901 human gastric adenocarcinoma cells via simultaneous induction of apoptosis and autophagy. Oncol Rep, 27(5):1481-7. doi: 10.3892/or.2012.1694

Shin YW, Bae EA, Cai XF, Lee JJ, and Kim DH. (2007). In vitro and in vivo antiallergic effect of the fructus of Evodia rutaecarpa and its constituents, Biological and Pharmaceutical Bulletin, 30(1):197–199, 2007.

Shyu KG, Lin S, Lee CC et al. (2006). Evodiamine inhibits in vitro angiogenesis: implication for anti-tumorgenicity. Life Sciences, 78(19):2234–2243.

Takada Y, Kobayashi Y, Aggarwal BB. (2005). Evodiamine Abolishes Constitutive and Inducible NF- κB Activation by Inhibiting IκBα Kinase Activation, Thereby Suppressing NF-κ B-regulated Antiapoptotic and Metastatic Gene Expression, Up-regulating Apoptosis, and Inhibiting Invasion. The Journal of Biological Chemistry, 280:17203-17212. doi: 10.1074/jbc.M500077200.

Tsai HP, Lin LW, Lai ZY et al. (2010). Immobilizing topoisomerase I on a surface plasmon resonance biosensor chip to screen for inhibitors. Journal of Biomedical Science, 17(1):49.

Wang C, Li S, Wang MW. (2010). Evodiamine-induced human melanoma A375-S2 cell death was mediated by PI3K/Akt/caspase and Fas-L/NF- κ B signaling pathways and augmented by ubiquitin-proteasome inhibition. Toxicology in Vitro, 24(3):898–904.

Wang KL, Hsia SM, Yeh JY, et al. (2013). Anti-Proliferative Effects of Evodiamine on Human Breast Cancer Cells. PLoS One, 8(6):e67297.

Wei WT, Chen H, Wang ZH, et al. (2012). Enhanced anti-tumor efficacy of gemcitabine by evodiamine on pancreatic cancer via regulating PI3K/Akt pathway. Int J Biol Sci, 8(1):1-14.

Yu H, Jin H, Gong W, Wang Z, Liang H. (2013). Pharmacological actions of multi-target-directed evodiamine. Molecules, 18(2):1826-43. doi: 10.3390/molecules18021826.

Yang J, Wu LJ, Tashino SI, et al. (2007). Critical roles of reactive oxygen species in mitochondrial permeability transition in mediating evodiamine-induced human melanoma A375-S2 cell apoptosis. Free Radical Research, 41(10):1099–1108.

Zhang Y, Wu LJ, Tashiro SI, Onodera S, Ikejima T. (2003). Intracellular regulation of evodiamine-induced A375-S2 cell death. Biological and Pharmaceutical Bulletin, 26(11):1543–1547.

Zhang Y, Zhang QH, Wu LJ, et al. (2004). Atypical apoptosis in L929 cells induced by evodiamine isolated from Evodia rutaecarpa. Journal of Asian Natural Products Research, 6(1):19–27.

A549, Akt, Andrographis paniculata, Anti-cancer, Anti-cancer effect, anti-inflammatory, Anti-metastatic, anti-oxidant, AP-1, apoptosis, apoptosis-inducing, c-Jun, Chapter 7 Isolates and Cancer Research, Colon Cancer or Colorectal cancer, cytotoxic, DR4, Immune, Immunomodulatory, induces apoptosis, Lung cancer, metastasis, p53, PI3K, PI3K/Akt, PI3K/Akt/AP-1, Rectal cancer, TNF, TRAIL

Andrographolide

March 27, 2014 brian

Cancer: Leukemia, colorectal, lung

Action: Immunomodulatory,anti-inflammatory,anti-metastatic

Andrographolide (Andro), a diterpenoid lactone isolated from a traditional herbal medicine Andrographis paniculata [(Burm. f.) Wall. Ex Nees], is known to possess multiple pharmacological activities. Andrographolide has been shown to exhibit antioxidative, anti-cancer, anti-inflammatory, anti-diabetes, and anti-aging properties (Trivedi et al., 2007; Chao et al., 2010).

Immunomodulatory Activity

The immunomodulatory activity of HN-02, an extract containing a mixture of andrographolides, was evaluated at 1.0, 1.5, and 2.5 mg/kg on different in vivo and in vitro experimental models. It was also found that HN-02 treatment stimulated phagocytosis in mice. A significant increase in total WBC count and relative weight of spleen and thymus was observed in mice during 30 days of treatment with HN-02.

The present experimental findings demonstrate that HN-02 has the ability to enhance immune function, possibly through modulation of immune responses altered during antigen interaction, and to reverse the immunosuppression induced by CYP (Naik, 2009).

The ethanol extract and purified diterpene andrographolides of Andrographis paniculata (Acanthaceae) induced significant stimulation of antibody and delayed type hypersensitivity (DTH) response to sheep red blood cells (SRBC) in mice. The plant preparations also stimulated non-specific immune response of the animals measured in terms of macrophage migration index (MMI) phagocytosis of Escherichia coli and proliferation of splenic lymphocytes. The stimulation of both antigen specific and non-specific immune response was, however, of lower order with andrographolide than with the ethanol extract, suggesting that substance(s) other than andrographolide present in the extract may also be contributing towards immunostimulation (Puri, 1993)

Anti-inflammatory and Leukemic Therapies

Andrographolide has been shown to attenuate MMP-9 expression, with its main mechanism likely involving the NF-κB signal pathway. These results provide new opportunities for the development of new anti-inflammatory and leukemic therapies. This activity was shown in a study in which andrographolide (1–50µM) exhibited concentration-dependent inhibition of MMP-9 activation, induced by either tumor necrosis factor-α (TNF-α), or lipopolysaccharide (LPS), in THP-1cells.

Anti-inflammatory

Lee et al (2012) found that andrographolide could significantly inhibit the degradation of inhibitor-κB-α (IκB-α) induced by TNF-α. They used electrophoretic mobility shift assay and reporter gene detection to show that andrographolide also markedly inhibited NF-signaling, anti-translocation and anti-activation. These results provide new opportunities for the development of new anti-inflammatory and leukemic therapies.

Lung Cancer Metastasis

Andrographolide is known to have the potential to be developed as a chemotherapeutic agent, in particular in the treatment of lung cancer. In order to understand the anti-cancer properties of andrographolide, its effect on migration and invasion in human lung cancer A549 cells was examined. The results of the wound-healing assay and the in vitro transwell assay revealed that andrographolide inhibited dose-dependently the migration and invasion of A549 cells under non-cytotoxic concentrations.

These results indicated that andrographolide exerted an inhibitory effect on the activity and the mRNA and protein levels of MMP-7, but not MMP-2 or MMP-9. The andrographolide-inhibited MMP-7 expression or activity appeared to occur via activator protein-1 (AP-1) because its DNA binding activity was suppressed by andrographolide. Additionally, the transfection of Akt over-expression vector (Akt1 cDNA) to A549 cells could result in an increase expression of MMP-7 concomitantly with a marked induction on cell invasion. These findings suggested that the inhibition on MMP-7 expression by andrographolide may be through suppression on PI3K/Akt/AP-1 signaling pathway, which in turn leads to the reduced invasiveness of the cancer cells (Lee, 2010).

Colorectal Cancer

Andrographolide has also been shown to have potent anti-cancer activity against human colorectal carcinoma Lovo cells by inhibiting cell-cycle progression. To further investigate the mechanism for the anti-cancer properties of andrographolide, it was used to examine the effect on migration and invasion of Lovo cells. The results of wound-healing assay and in vitro transwell assay revealed that andrographolide inhibited dose-dependently the migration and invasion of Lovo cells under non-cytotoxic concentrations.

The down-regulation of MMP-7 appeared to be via the inactivation of activator protein-1 (AP-1) since the treatment with andrographolide suppressed the nuclear protein level of AP-1, which was accompanied by a decrease in DNA-binding level of the factor. Taken together, these results indicate that andrographolide reduces the MMP-7-mediated cellular events in Lovo cells, and provide a new mechanism for its anti-cancer activity (Shi, 2009)

Anti-inflammatory, Induces Apoptosis

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is an important member of the tumor necrosis factor subfamily with great potential in cancer therapy; additionally andrographolide is known to possess potent anti-inflammatory and anti-cancer activities which may be attributed to its action on TRAIL. It has been shown that pre-treatment with andrographolide significantly enhances TRAIL-induced apoptosis in various human cancer cell lines, including those TRAIL-resistant cells.

Pre-treatment with an anti-oxidant (N-acetylcysteine) or a c-Jun NH(2)-terminal kinase inhibitor (SP600125) effectively prevented andrographolide-induced p53 activation and DR4 up-regulation and eventually blocked the andrographolide-induced sensitization on TRAIL-induced apoptosis. Taken together, these results present a novel anti-cancer effect of andrographolide and support its potential application in cancer therapy to overcome TRAIL resistance (Zhou, 2008).

References

Chao HP, Kuo CD, Chiu JH, Fu SL. (2010). Andrographolide exhibits anti-invasive activity against colon cancer cells via inhibition of MMP2 activity. Planta Medica, 76(16):1827–1833. doi: 10.1055/s-0030-1250039.

Lee WR, Chung CL, Hsiao CJ, et al. (2012). Suppression of matrix metalloproteinase-9 expression by andrographolide in human monocytic THP-1 cells via inhibition of NF- κB activation. Phytomedicine, 19(3):270-277. doi: 10.1016/j.phymed.2011.11.012

Lee YC, Lin HH, Hsu CH, et al. (2010). Inhibitory effects of andrographolide on migration and invasion in human non-small-cell lung cancer A549 cells via down-regulation of PI3K/Akt signaling pathway. Eur J Pharmacol, 632(1-3):23-32. doi: 10.1016/j.ejphar.2010.01.009.

Naik SR, Hule A. (2009). Evaluation of Immunomodulatory Activity of an Extract of Andrographolides from Andographis paniculata. Planta Med, 75(8):785-91. doi: 10.1055/s-0029-1185398.

Puri A, Saxena R, Saxena RP, et al. (1993). Immunostimulant agents from Andrographis paniculata. J Nat Prod, 56(7):995-9.

Shi MD, Lin HH, Chiang TA, et al. (2009). Andrographolide could inhibit human colorectal carcinoma Lovo cells migration and invasion via down-regulation of MMP-7 expression. Chem Biol Interact, 180(3):344-52. doi: 10.1016/j.cbi.2009.04.011.

Trivedi NP, Rawal UM, Patel BP. (2007). Hepato-protective effect of andrographolide against hexachlorocyclohexane- induced oxidative injury. Integrative Cancer Therapies, 6(3):271–280. doi: 10.1177/1534735407305985.

Zhou J, Lu GD, Ong CS, Ong CN, Shen HM. (2008). Andrographolide sensitizes cancer cells to TRAIL-induced apoptosis via p53-mediated death receptor 4 up-regulation. Mol Cancer Ther, 7(7):2170-80. doi: 10.1158/1535-7163.MCT-08-0071.

Akt, angiogenesis, Anti-estrogenic, apoptosis, Apoptotic, Astragalus membranaceus, BAX, Breast cancer, Causes cell-cycle arrest, cell-cycle arrest, Cervical cancer, Chapter 7 Isolates and Cancer Research, Colon Cancer or Colorectal cancer, ER, ER-positive, ERK1, G0/G1, G1, growth-inhibitory, inhibits angiogenesis, MAPK, MCF-7, MCF-7 and T47D, MDR, PI3K, PI3K/Akt, Pro-apoptotic, Prostate cancer, ROS, VEGF, VEGF

Formononetin

March 27, 2014 brian

Cancer: Prostate, colorectal., breast, cervical

Action: Cell-cycle arrest, MDR, growth-inhibitory

Estrogenic or Anti-estrogenic

Formononetin is one of the main active components of red clover plants, and considered as a phytoestrogen. Its pharmacological effects in vivo may be either estrogenic or anti-estrogenic, mainly depending upon the estrogen levels (Chen & Sun., 2012).

Cell-cycle Arrest, Prostate Cancer

Formononetin has been demonstrated to cause cell-cycle arrest at the G0/G1 phase by inactivating insulin-like growth factor 1(IGF1)/IGF1R-phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt) pathway in MCF-7 cells. The molecular mechanisms involved in the effect of formononetin on prostate cancer cells were hence investigated. These results suggest that higher concentrations of formononetin inhibit the proliferation of prostate cancer cells (LNCaP and PC-3), while the most striking effect was observed in LNCaP cells.

From these results, it was concluded that the induced apoptosis effect of formononetin on human prostate cancer cells was related to ERK1/2 MAPK-Bax pathway. Considering that red clover plants were widely used clinically, these results provided the foundation for future development of different concentrations of formononetin for treatment of prostate cancer (Ye et al., 2012).

Colon Cancer

Formononetin is a novel herbal isoflavonoid isolated from Astragalus membranaceus, a medicinal plant that possesses anti-tumorigenic properties. It has been demonstrated that formononetin initiates growth-inhibitory and pro-apoptotic activities in human colon cancer cells. The potential of formononetin in controlling angiogenesis and tumor cell invasiveness has further been examined in human colon cancer cells and tumor xenografts. The results showed that formononetin downregulated the expression of the key pro-angiogenic factors, including vascular endothelial growth factor (VEGF) and matrix metalloproteinases. The tumor size and the number of proliferating cells were reduced in the tumor tissues obtained from the formononetin-treated group.

The serum VEGF level was also reduced in the drug-treated animals when compared to the controls. These findings suggest that formononetin inhibits angiogenesis and tumor cell invasion, and thus support its use in the treatment of advanced and metastatic colon cancers (Auyeung et al., 2012).

Cervical Cancer

Formononetin may potentiate the cytotoxicity of epirubicin in HeLa cells through the ROS-mediated MRP inhibition and concurrent activation of the mitochondrial and death receptor pathways of apoptosis. Hence, the circumvention of pump and non-pump resistance using formononetin and epirubicin may pave the way for a powerful chemotherapeutic regimen for treating human cervical cancer (Lo et al., 2013).

Breast Cancer

Recent studies by Chen & Sun (2012) suggest that formononetin inactivated IGF1/IGF1R-PI3K/Akt pathways and decreased cyclin D1 mRNA and protein expression in human breast cancer cells in vitro and in vivo. In their present study, they further investigated the molecular mechanisms involved in the induced apoptosis effect of formononetin on breast cancer cells and formononetin inhibited the proliferation of ER-positive MCF-7 cells and T47D cells. The induced apoptosis effect of formononetin on human breast cancer cells was related to Ras-p38MAPK pathway.

Formononetin causes cell-cycle arrest at the G0/G1 phase by inactivating IGF1/IGF1R-PI3K/Akt pathways and decreasing cyclin D1 mRNA and protein expression, indicating the use of formononetin in the prevention of breast cancer carcinogenesis (Chen et al., 2011).

References

Auyeung KK, Law PC, Ko JK. (2012). Novel anti-angiogenic effects of formononetin in human colon cancer cells and tumor xenograft. Oncol Rep, 28(6):2188-94. doi: 10.3892/or.2012.2056.

Chen J, Zeng J, Xin M, Huang W, Chen X. (2011). Formononetin induces cell-cycle arrest of human breast cancer cells via IGF1/PI3K/Akt pathways in vitro and in vivo. Horm Metab Res, 43(10):681-6. doi: 10.1055/s-0031-1286306.

Chen J, Sun L. (2012). Formononetin-induced apoptosis by activation of Ras/p38 mitogen-activated protein kinase in estrogen receptor-positive human breast cancer cells. Horm Metab Res, 44(13):943-8. doi: 10.1055/s-0032-1321818.

Lo YL, Wang W. (2013). Formononetin potentiates epirubicin-induced apoptosis via ROS production in HeLa cells in vitro. Chem Biol Interact, 205(3):188-97. doi: 10.1016/j.cbi.2013.07.003.

Ye Y, Hou R, Chen J, et al. (2012). Formononetin-induced apoptosis of human prostate cancer cells through ERK1/2 mitogen-activated protein kinase inactivation. Horm Metab Res, 44(4):263-7. doi: 10.1055/s-0032-1301922.

5-LOX, ABC, ABCG2, Akt, angiogenesis, anti-apoptotic, Anti-cancer, anti-inflammatory, anti-oxidant, anti-proliferative, AP-1, apoptosis, apoptosis-inducing, Apoptotic, attenuation of immune suppression, Bcl-2, Breast cancer, cancer stem cells, Chapter 7 Isolates and Cancer Research, chemo-preventive, chemo-preventive activity, Chemoprevention, COC1/DDP, COX-2, Curcuma longa, CXCR-4, DR5, EGFR, Genitourinary cancers, HER-2, IL-1, IL-6, Immune, inflammation, KBV20C, Lung cancer, Lymphoma, MDR, Melanoma, metastasis, Neurological cancers, Neuropathy, Notch, Ovarian cancer, p53, Pancreatic cancer, PI3K, PI3K/Akt, Prostate cancer, Sarcoma, SGC7901/VCR, Squamous cell carcinoma, STAT, TNF, TRAIL, tumor-inhibitory, VEGF, VEGF

Curcumin

March 27, 2014 brian

Cancer: Colorectal., prostate, pancreatic

Action: MDR, chemo-preventive activity, anti-inflammatory, attenuation of immune suppression

Chemo-preventive Activity

Curcumin is a naturally occurring, dietary polyphenolic phytochemical that is under preclinical trial evaluation for cancer-preventive drug development. It is derived from the rhizome of Curcuma longa L. and has both anti-oxidant and anti-inflammatory properties; it inhibits chemically-induced carcinogenesis in the skin, forestomach, and colon when it is administered during initiation and/or postinitiation stages. Chemo-preventive activity of curcumin is observed when it is administered prior to, during, and after carcinogen treatment as well as when it is given only during the promotion/progression phase (starting late in premalignant stage) of colon carcinogenesis (Kawamori et al., 1999)

Anti-inflammatory

With respect to inflammation, in vitro, it inhibits the activation of free radical-activated transcription factors, such as nuclear factor κB (NFκB) and AP-1, and reduces the production of pro-inflammatory cytokines such as tumor necrosis factor-α (TNFα), interleukin-1β (IL-1β), and interleukin-8 (Chan et al., 1998)

Prostate Cancer

In addition, NF-kappaB and AP-1 may play a role in the survival of prostate cancer cells, and curcumin may abrogate their survival mechanisms (Mukhopadhyay et al., 2001).

Pancreatic Cancer

In patients suffering from pancreatic cancer, orally-administered curcumin was found to be well-tolerated and despite limited absorption, had a reasonable impact on biological activity in some patients. This was attributed to its potent nuclear factor-kappaB (NF-kappaB) and tumor-inhibitory properties, against advanced pancreatic cancer (Dhillon et al., 2008)

MDR

Curcumin, the major component in Curcuma longa (Jianghuang), inhibited the transport activity of all three major ABC transporters, i.e. Pgp, MRP1 and ABCG2 (Ganta et al., 2009).

Curcumin reversed MDR of doxorubicin or daunorubicin in K562/DOX cell line and decreased Pgp expression in a time-dependent manner (Chang et al., 2006). Curcumin enhanced the sensitivity to vincristine by the inhibition of Pgp in SGC7901/VCR cell line (Tang et al., 2005). Moreover, curcumin was useful in reversing MDR associated with a decrease in bcl-2 and survivin expression but an increase in caspase-3 expression in COC1/DDP cell line (Ying et al., 2007).

The cytotoxicity of vincristine and paclitaxel were also partially restored by curcumin in resistant KBV20C cell line. Curcumin derivatives reversed MDR by inhibiting Pgp efflux (Um et al., 2008). A chlorine substituent at the meta-or para-position on benzamide improved MDR reversal [72]. Bisdemethoxycurcumin modified from curcumin resulted in greater inhibition of Pgp expression (Limtrakul et al., 2004).

Attenuation of Immune Suppression

Curcumin (a chalcone) exhibited toxicity to human neural stem cells (hNSCs). Although oridonin (a diterpene) showed a null toxicity toward hNSCs, it repressed the enzymatic function only marginally in contrast to its potent cytotoxicity in various cancer cell lines. While the mode of action of the enzyme-polyphenol complex awaits to be investigated, the sensitivity of enzyme inhibition was compared to the anti-proliferative activities toward three cancer cell lines.

The IC50s obtained from both sets of the experiments indicate that they are in the vicinity of micromolar concentration with the enzyme inhibition slightly more active.

These results suggest that attenuation of immune suppression via inhibition of IDO-1 enzyme activity may be one of the important mechanisms of polyphenols in chemoprevention or combinatorial cancer therapy (Chen et al., 2012).

Cancer Stem Cells

In cancers that appear to follow the stem cell model, pathways such as Wnt, Notch and Hedgehog may be targeted with natural compounds such as curcumin or drugs to reduce the risk of initiation of new tumors. Disease progression of established tumors could also potentially be inhibited by targeting the tumorigenic stem cells alone, rather than aiming to reduce overall tumor size.

Cancer treatments could be evaluated by assessing stem cell markers before and after treatment. Targeted stem cell specific treatment of cancers may not result in 'complete' or 'partial' responses radiologically, as stem cell targeting may not reduce the tumor bulk, but eliminate further tumorigenic potential. These changes are discussed using breast, pancreatic, and lung cancer as examples (Reddy et al., 2011).

Multiple Cancer Effects; Cell-signaling

Curcumin has been shown to interfere with multiple cell signaling pathways, including cell-cycle (cyclin D1 and cyclin E), apoptosis (activation of caspases and down-regulation of anti-apoptotic gene products), proliferation (HER-2, EGFR, and AP-1), survival (PI3K/AKT pathway), invasion (MMP-9 and adhesion molecules), angiogenesis (VEGF), metastasis (CXCR-4) and inflammation (NF- κB, TNF, IL-6, IL-1, COX-2, and 5-LOX).

The activity of curcumin reported against leukemia and lymphoma, gastrointestinal cancers, genitourinary cancers, breast cancer, ovarian cancer, head and neck squamous cell carcinoma, lung cancer, melanoma, neurological cancers, and sarcoma reflects its ability to affect multiple targets (Anand et al., 2008).

Anti-inflammatory; Cell-signaling

Curcumin, a liposoluble polyphenolic pigment isolated from the rhizomes of Curcuma longa L. (Zingiberaceae), is another potential candidate for new anti-cancer drug development. Curcumin has been reported to influence many cell-signaling pathways involved in tumor initiation and proliferation. Curcumin inhibits COX-2 activity, cyclin D1 and MMPs overexpresion, NF-kB, STAT and TNF-alpha signaling pathways and regulates the expression of p53 tumor suppressing gene.

Curcumin is well-tolerated but has a reduced systemic bioavailability. Polycurcumins (PCurc 8) and curcumin encapsulated in biodegradable polymeric nanoparticles showed higher bioavailability than curcumin together with a significant tumor growth inhibition in both in vitro and in vivo studies (Cretu et al., 2012). Curcumin also sensitizes tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis through reactive oxygen species-mediated up-regulation of death receptor 5 (DR5) (Jung et al., 2005).

Curcumin and bioavailability

Curcumin, a major constituent of the spice turmeric, suppresses expression of the enzyme cyclooxygenase 2 (Cox-2) and has cancer chemo-preventive properties in rodents. It possesses poor systemic availability. Marczylo et al. (2007) explored whether formulation with phosphatidylcholine increases the oral bioavailability or affects the metabolite profile of curcumin. Their results suggest that curcumin formulated with phosphatidylcholine furnishes higher systemic levels of parent agent than unformulated curcumin.

Curcuminoids are poorly water-soluble compounds and to overcome some of the drawbacks of curcuminoids, Aditya et al. (2012) explored the potential of liposomes for the intravenous delivery of curcuminoids. The curcuminoids-loaded liposomes were formulated from phosphatidylcholine (soy PC). Curcumin/curcuminoids were encapsulated in phosphatidylcholine vesicles with high yields. Vesicles in the size range around 200 nm were selected for stability and cell experiments. Liposomal curcumin were found to be twofold to sixfold more potent than corresponding curcuminoids. Moreover, the mixture of curcuminoids was found to be more potent than pure curcumin in regard to the anti-oxidant and anti-inflammatory activities (Basnet et al., 2012). Results suggest that the curcumin-phosphatidylcholine complex improves the survival rate by increasing the anti-oxidant activity (Inokuma et al., 2012). Recent clinical trials on the effectiveness of phosphatidylcholine formulated curcumin in treating eye diseases have also shown promising results, making curcumin a potent therapeutic drug candidate for inflammatory and degenerative retinal and eye diseases (Wang et al., 2012). Data demonstrate that treatment with curcumin dissolved in sesame oil or phosphatidylcholine curcumin improves the peripheral neuropathy of R98C mice by alleviating endoplasmic reticulum stress, by reducing the activation of unfolded protein response (Patzk- et al., 2012).

References

Aditya NP, Chimote G, Gunalan K, et al. (2012). Curcuminoids-loaded liposomes in combination with arteether protects against Plasmodium berghei infection in mice. Exp Parasitol, 131(3):292-9. doi: 10.1016/j.exppara.2012.04.010.

Anand P, Sundaram C, Jhurani S, Kunnumakkara AB, Aggarwal BB. (2008). Curcumin and cancer: An 'old-age' disease with an 'age-old' solution. Cancer Letters, 267(1):133–164. doi: 10.1016/j.canlet.2008.03.025.

Basnet P, Hussain H, Tho I, Skalko-Basnet N. (2012). Liposomal delivery system enhances anti-inflammatory properties of curcumin. J Pharm Sci, 101(2):598-609. doi: 10.1002/jps.22785.

Chan MY, Huang HI, Fenton MR, Fong D. (1998). In Vivo Inhibition of Nitric Oxide Synthase Gene Expression by Curcumin, a Cancer-preventive Natural Product with Anti-Inflammatory Properties. Biochemical Pharmacology, 55(12), 1955-1962.

Chang HY, Pan KL, Ma FC, et al. (2006). The study on reversing mechanism of Multi-drug resistance of K562/DOX cell line by curcumin and erythromycin. Chin J Hem, 27(4):254-258.

Chen SS, Corteling R, Stevanato L, Sinden J. (2012). Polyphenols Inhibit Indoleamine 3,5-Dioxygenase-1 Enzymatic Activity — A Role of Immunomodulation in Chemoprevention. Discovery Medicine.

Cre ţ u E, Trifan A, Vasincu A, Miron A. (2012). Plant-derived anti-cancer agents – curcumin in cancer prevention and treatment. Rev Med Chir Soc Med Nat Iasi, 116(4):1223-9.

Dhillon N, Aggarwal BB, Newman RA, et al. (2008). Phase II trial of curcumin in patients with advanced pancreatic cancer. Clin Cancer Res,14(14):4491-9. doi: 10.1158/1078-0432.CCR-08-0024.

Ganta S, Amiji M. (2009). Coadministration of paclitaxel and curcumin in nanoemulsion formulations To overcome Multi-drug resistance in tumor cells. Mol Pharm, 6(3):928-939. doi: 10.1021/mp800240j.

Inokuma T, Yamanouchi K, Tomonaga T, et al. (2012). Curcumin improves the survival rate after a massive hepatectomy in rats. Hepatogastroenterology, 59(119):2243-7. doi: 10.5754/hge10650.

Jung EM, Lim JH, Lee TJ, et al. (2005). Curcumin sensitizes tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis through reactive oxygen species-mediated up-regulation of death receptor 5 (DR5). Carcinogenesis, 26(11):1905-1913.