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Old 12-14-2009, 01:52 PM   #1
Rich66
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Join Date: Feb 2008
Location: South East Wisconsin
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Milk thistle

(monotherapy, liver protectant, synergy w/Dox,Cis,Carb, antinflamm/Il-8, Anti CD44 CSC(?), AntiAngio, mTOR, Vimentin, mmp2, Hif1, Cx2, brain barrier, phytosome best)



A phytosome formulation of milk thistle for sale: HERE




Anticancer Agents Med Chem. 2009 Dec 16. [Epub ahead of print]
Silibinin - A Promising New Treatment for Cancer.

Cheung CW, Gibbons N, Johnson DW, Nicol DL.
Departments of Renal Medicine, University of Queensland at Princess Alexandra Hospital, Brisbane, Queensland, Australia. catherine_cheung@health.qld.gov.au.
Silymarin and its major constituent, Silibinin, are extracts from the medicinal plant Silybum marianum (milk thistle) and have traditionally been used for the treatment of liver diseases. Recently, these orally active, flavonoid agents have also been shown to exert significant anti-neoplastic effects in a variety of in vitro and in vivo cancer models, including skin, breast, lung, colon, bladder, prostate and kidney carcinomas. The aim of the present review is to examine the pharmacokinetics, mechanisms, effectiveness and adverse effects of silibinin's anti-cancer actions reported to date in pre-clinical and clinical trials. The review will also discuss the results of current research efforts seeking to determine the extent to which the effectiveness of silibinin as an adjunct cancer treatment is influenced by such factors as histologic subtype, hormonal status, stromal interactions and drug metabolising gene polymorphisms. The results of these studies may help to more precisely target and dose silibinin therapy to optimise clinical outcomes for oncology patients.

PMID: 20015009 [PubMed - as supplied by publisher]




Cancer Lett. 2008 Oct 8;269(2):352-62. Epub 2008 May 9.
Multitargeted therapy of cancer by silymarin.

Ramasamy K, Agarwal R.
Department of Pharmaceutical Sciences, School of Pharmacy, University of Colorado Denver, 4200 East Ninth Street, Box C238, Denver, CO 80262, USA.
Silymarin, a flavonolignan from milk thistle (Silybum marianum) plant, is used for the protection against various liver conditions in both clinical settings and experimental models. In this review, we summarize the recent investigations and mechanistic studies regarding possible molecular targets of silymarin for cancer prevention. Number of studies has established the cancer chemopreventive role of silymarin in both in vivo and in vitro models. Silymarin modulates imbalance between cell survival and apoptosis through interference with the expressions of cell cycle regulators and proteins involved in apoptosis. In addition, silymarin also showed anti-inflammatory as well as anti-metastatic activity. Further, the protective effects of silymarin and its major active constituent, silibinin, studied in various tissues, suggest a clinical application in cancer patients as an adjunct to established therapies, to prevent or reduce chemotherapy as well as radiotherapy-induced toxicity. This review focuses on the chemistry and analogues of silymarin, multiple possible molecular mechanisms, in vitro as well as in vivo anti-cancer activities, and studies on human clinical trials.

PMID: 18472213 [PubMed - indexed for MEDLINE]



Mol Cancer Ther. 2009 Jun;8(6):1606-12. Epub 2009 Jun 9.
Silibinin inhibits translation initiation: implications for anticancer therapy.

Lin CJ, Sukarieh R, Pelletier J.
McGill University, 3655 Promenade Sir William Osler, Montreal, Quebec, Canada.
Silibinin is a nontoxic flavonoid reported to have anticancer properties. In this study, we show that silibinin exhibits antiproliferative activity on MCF-7 breast cancer cells. Exposure to silibinin leads to a concentration-dependent decrease in global protein synthesis associated with reduced levels of eukaryotic initiation factor 4F complex. Moreover, polysome profile analysis of silibinin-treated cells shows a decrease in polysome content and translation of cyclin D1 mRNA. Silibinin exerts its effects on translation initiation by inhibiting the mammalian target of rapamycin signaling pathway by acting upstream of TSC2. Our results show that silibinin blocks mammalian target of rapamycin signaling with a concomitant reduction in translation initiation, thus providing a possible molecular mechanism of how silibinin can inhibit growth of transformed cells.

PMID: 19509268 [PubMed - indexed for MEDLINE]




Phytomedicine. 2009 Jun;16(6-7):573-80. Epub 2009 Jan 31.
Silibinin prevents TPA-induced MMP-9 expression and VEGF secretion by inactivation of the Raf/MEK/ERK pathway in MCF-7 human breast cancer cells.

Kim S, Choi JH, Lim HI, Lee SK, Kim WW, Kim JS, Kim JH, Choe JH, Yang JH, Nam SJ, Lee JE.
Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, 50 Ilwon-dong, Kangnam-gu, Seoul 135-710, South Korea.
Matrix metalloproteinase-9 (MMP-9) and vascular endothelial growth factor (VEGF) expression are pivotal steps in cancer metastasis. Herein, we investigated the effect of silibinin, a major constituent (flavanolignan) of the fruits of Silybum marianum, on 12-O-tetradecanoyl phorbol-13-acetate (TPA)-induced MMP-9 and VEGF expression in MCF-7 human breast cancer cells. The expression of MMP-9 and VEGF in response to TPA was increased, whereas TPA-induced MMP-9 and VEGF expression was decreased by silibinin. To investigate the regulatory mechanism of silibinin on TPA-induced MMP-9 and VEGF expression, we pretreated cells with various inhibitors, such as UO126 (MEK1/2 inhibitor), SP600125 (JNK inhibitor), and SB203580 (p38 inhibitor). Interestingly, TPA-induced MMP-9 expression was significantly inhibited by UO126, but not by SP600125 and SB203580. In addition, we pretreated cells with 100 microM silibinin prior to TPA treatment. TPA-induced MEK and ERK phosphorylation was significantly decreased by silibinin in MCF7 cells. TPA-induced VEGF expression was also suppressed by UO126. On the other hand, we found that adenoviral constitutive active-MEK (Ad-CA-MEK) significantly increased MMP-9 and VEGF expression. Taken together, we suggest that the inhibition of TPA-induced MMP-9 and VEGF expression by silibinin is mediated by the suppression of the Raf/MEK/ERK pathway in MCF-7 breast cancer cells.

PMID: 19181503 [PubMed - indexed for MEDLINE]





Expert Opin Investig Drugs. 2010 Feb;19(2):243-55.
Targeting silibinin in the antiproliferative pathway.

Li L, Zeng J, Gao Y, He D.
The First Hospital of Xi'an Jiaotong University, Department of Urology, 277 Yanta West Road, Xi'an 710061, People's Republic of China.
IMPORTANCE OF THE FIELD: Due to the failure and severe toxicity of cancer chemotherapy, silibinin, a natural flavonoid from the seeds of milk thistle, has recently received more attention for its potential anticancer and nontoxic roles in animals and humans. Silibinin has clearly demonstrated inhibition of multiple cancer cell signaling pathways, including growth inhibition, inhibition of angiogenesis, chemosensitization, and inhibition of invasion and metastasis. Cumulative evidence implicates that silibinin is a potential agent for cancer chemoprevention and chemotherapy. AREAS COVERED IN THIS REVIEW: Our aim is to discuss the recent progress of silibinin in regulating multiple anticancer proliferative signaling pathways; the review covers literature mainly from the past 3 - 5 years. WHAT THE READER WILL GAIN: One of the strategies for tumor therapy is eradication of cancer cells through targeting specific cell-proliferative pathways. This review highlights the current knowledge of silibinin in regulating multiple cellular proliferative pathways in cancer cells, including receptor tyrosine kinases, androgen receptor, STATs, NF-kappaB, cell cycle regulatory and apoptotic signaling pathways. TAKE HOME MESSAGE: The molecular mechanisms of silibinin-mediated antiproliferative effects are mainly via receptor tyrosine kinases, androgen receptor, STATs, NF-kappaB, cell cycle regulatory and apoptotic signaling pathways in various cancer cells. Targeting inhibition of proliferative pathways through silibinin treatment may provide a new approach for improving chemopreventive and chemotherapeutic effects.




Oncogene. 2009 Jan 22;28(3):313-24. Epub 2008 Nov 3.
Silibinin inhibits hypoxia-inducible factor-1alpha and mTOR/p70S6K/4E-BP1 signalling pathway in human cervical and hepatoma cancer cells: implications for anticancer therapy.

García-Maceira P, Mateo J.
Department of Regenerative Cardiology, Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain.
The hypoxia-inducible factor 1 (HIF-1) plays a critical role for tumour adaptation to microenvironmental hypoxia, and represents an appealing chemotherapeutic target. Silibinin is a nontoxic flavonoid reported to exhibit anticancer properties. However, the mechanisms by which silibinin inhibits tumour growth are not fully understood. In this study, silibinin was found to inhibit hypoxia-induced HIF-1alpha accumulation and HIF-1 transcriptional activity in human cervical (HeLa) and hepatoma (Hep3B) cells. Neither HIF-1alpha protein degradation rate nor HIF-1alpha steady-state mRNA level was affected by silibinin. Rather, we found that suppression of HIF-1alpha accumulation by silibinin correlated with strong dephosphorylation of mammalian target of rapamycin (mTOR) and its effectors ribosomal protein S6 kinase (p70S6K) and eukaryotic initiation factor 4E-binding protein-1 (4E-BP1), a pathway known to regulate HIF-1alpha expression at the translational level. Silibinin also activated Akt, a mechanistic feature exhibited by established mTOR inhibitors in many tumour cells. Moreover, silibinin reduced hypoxia-induced vascular endothelial growth factor (VEGF) release by HeLa and Hep3B cells, and this effect was potentiated by the PI3K/Akt inhibitor LY294002. Finally, silibinin was found to be a potent inhibitor of cell proliferation. These results show that silibinin is an effective inhibitor of HIF-1 and provide new perspectives into the mechanism of its anticancer activity.

PMID: 18978810 [PubMed - indexed for MEDLINE]




J Ethnopharmacol. 2009 Nov 12;126(2):252-7. Epub 2009 Aug 26.
Silibinin prevents TPA-induced MMP-9 expression by down-regulation of COX-2 in human breast cancer cells.

Kim S, Kim SH, Hur SM, Lee SK, Kim WW, Kim JS, Kim JH, Choe JH, Nam SJ, Lee JE, Yang JH.
Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Kangnam-gu, Seoul 135-710, South Korea.
ETHNOPHARMACOLOGICAL RELEVANCE: The expression of matrix metalloproteinase-9 (MMP-9) and cyclooxygenase-2 (COX-2) are pivotal steps in breast cancer pathogenesis. In a previous study, we reported that silibinin suppresses TPA-induced MMP-9 expression through the Raf/MEK/ERK pathway. AIMS OF THE STUDY: Herein we determined the co-relationship between MMP-9 and COX-2, as well as the effect of silibinin on 12-O-tetradecanoyl phorbol-13-acetate (TPA)-induced MMP-9 and COX-2 expression in the human breast cancer cells, MCF-7 and MDA-MB231. METHODS: The toxicity of silibinin was evaluated by Quick Cell Proliferation Assay Kit II. MMP-9 and COX-2 expression were analyzed by Zymography and Western blotting, respectively. Adenoviral constitutively active (CA)-MEK was used to activate MEK/ERK pathway. RESULTS: The expression of MMP-9 and COX-2 in response to TPA was increased, whereas TPA-induced MMP-9 and COX-2 expression was decreased by silibinin. Our results showed that TPA-induced MMP-9 expression was inhibited by celecoxib in a dose-dependent fashion, but not MMP-1-expression. Both MMP-9 and COX-2 expression were significantly increased by CA-MEK overexpression. In contrast, TPA-induced MMP-9 and COX-2 expression was decreased by UO126 (MEK 1/2 inhibitor). CONCLUSION: Silibinin down-regulates TPA-induced MMP-9 expression through inhibition of COX-2 expression in breast cancer cells.

PMID: 19715751 [PubMed - in process]




Phytomedicine. 2009 Jun;16(6-7):573-80. Epub 2009 Jan 31.
Silibinin prevents TPA-induced MMP-9 expression and VEGF secretion by inactivation of the Raf/MEK/ERK pathway in MCF-7 human breast cancer cells.

Kim S, Choi JH, Lim HI, Lee SK, Kim WW, Kim JS, Kim JH, Choe JH, Yang JH, Nam SJ, Lee JE.
Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, 50 Ilwon-dong, Kangnam-gu, Seoul 135-710, South Korea.
Matrix metalloproteinase-9 (MMP-9) and vascular endothelial growth factor (VEGF) expression are pivotal steps in cancer metastasis. Herein, we investigated the effect of silibinin, a major constituent (flavanolignan) of the fruits of Silybum marianum, on 12-O-tetradecanoyl phorbol-13-acetate (TPA)-induced MMP-9 and VEGF expression in MCF-7 human breast cancer cells. The expression of MMP-9 and VEGF in response to TPA was increased, whereas TPA-induced MMP-9 and VEGF expression was decreased by silibinin. To investigate the regulatory mechanism of silibinin on TPA-induced MMP-9 and VEGF expression, we pretreated cells with various inhibitors, such as UO126 (MEK1/2 inhibitor), SP600125 (JNK inhibitor), and SB203580 (p38 inhibitor). Interestingly, TPA-induced MMP-9 expression was significantly inhibited by UO126, but not by SP600125 and SB203580. In addition, we pretreated cells with 100 microM silibinin prior to TPA treatment. TPA-induced MEK and ERK phosphorylation was significantly decreased by silibinin in MCF7 cells. TPA-induced VEGF expression was also suppressed by UO126. On the other hand, we found that adenoviral constitutive active-MEK (Ad-CA-MEK) significantly increased MMP-9 and VEGF expression. Taken together, we suggest that the inhibition of TPA-induced MMP-9 and VEGF expression by silibinin is mediated by the suppression of the Raf/MEK/ERK pathway in MCF-7 breast cancer cells.

PMID: 19181503 [PubMed - indexed for MEDLINE]




Acta Pharmacol Sin. 2007 Sep;28(9):1466-75.
Combinatorial strategies for cancer eradication by silibinin and cytotoxic agents: efficacy and mechanisms.

FULL TEXT (free)
Starts with a good explanation of chemo types, and illustration of mechanisms and discussion of resistance mechanisms.


Raina K, Agarwal R.
Department of Pharmaceutical Sciences, School of Pharmacy, University of Colorado Health Sciences Center, Denver, CO 80262, USA.
In an effort to develop effective alternative strategies that increase the therapeutic efficacy and minimize the systemic toxicity of chemotherapeutic agents, more efforts are being directed towards the investigation of dietary supplements and other phytotherapeutic agents for their synergistic efficacy in combination with anticancer drugs. One such agent is silibinin, which has shown promising chemopreventive and anticancer effects in various in vitro and in vivo studies. The present review summarizes the effects of the combination of silibinin and chemotherapeutic drugs on the growth inhibition, cell cycle regulation, and apoptosis induction in prostate, breast, and lung cancer systems. Together, the results indicate a synergistic effect of silibinin on growth inhibition, reversal of chemoresistance, apoptosis induction, and a strong increase in G2-M checkpoint arrest when given in combination with these drugs. These results are highly significant with respect to the combined chemotherapy approach, wherein the criteria for combination is that the response has to be synergistic and that the drugs should not share common mechanisms of resistance and not overlap in their major side-effects.

PMID: 17723180 [PubMed - indexed for MEDLINE]

Quote:
Studies conducted by us and others have shown that silibinin and silymarin have anticancer activity against breast, skin, androgen-dependent andindependent prostate, cervical, bladder, hepatocellular, colon, ovarian, and lung cancer cells in culture and several in vivo animal cancer model systems[26]. The administration of these compounds to various laboratory animals has not shown any toxic or adverse effects in various acute, subchronic and chronic tests; there is no known LD50 for silymarin and silibinin in these animals[30,31]. This is also supported by our in vivo studies in animal models where we have used high doses of silibinin, up to 2 g/kg per d by oral gavage or 1%(w/w) in the diet, and observed no apparent signs of toxicity [27,29].
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Quote:
Figure2
Combinations of cisplatin, carboplatin, and doxorubicin with silibinin showed strong synergistic effects on cell growth inhibition in both estrogen-dependant MCF-7 and -independent MDA–MB468 human breast carcinoma cell lines. A combination of silibinin and doxorubicin also showed strong apoptotic death in both cell lines. Silibinin and carboplatin combinations increased the apoptotic effect in MCF-7 cells only, while the combination with
cisplatin did not show any additional apoptotic effect in any of these cell lines.
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Quote:
We also assessed the synergistic effect of silibinin with chemotherapy agents in estrogen-dependant MCF-7 and -independent MDA–MB468 human breast carcinoma cell lines (Figure 2) [39]. In these cell lines, extensive dose- and time dependant studies were initially carried out with the single agents followed by several combinations (10–100 μmol/L) of silibinin with doxorubicin (10–75 nmol/L), cisplatin (0.2–2μg/mL), and carboplatin (2–20 μg/mL) to assess their synergistic/additive or antagonistic effect towards cell growth inhibition and apoptotic death. Combinations of these 3 drugs with silibinin showed strong synergistic effects on cell growth inhibition in both the cell lines, however, the strongest effect was due to a combination of 75 nmol/L doxorubicin and 100 μmol/L silibinin (CI: 0.35 for MCF-7 cells and CI: 0.45 for MDA–MB468 cells).
A combination of silibinin and doxorubicin also showed strong apoptotic death in both the
cell lines.
The silibinin and carboplatin combinations increased the apoptotic effect in MCF-7 cells only, while the combination with cisplatin did not show any additional apoptotic effect in any of these cell lines.
<
Quote:
we emphasize that silibinin is an ideal candidate to be used in clinical combination with the chemotherapeutic drugs which would increase their therapeutic efficacy and at the same time reduce the adverse effects associated with their high doses.





Herb May Counter Liver Damage From Chemo


Milk thistle appears to reduce liver inflammation in cancer patients, researchers say

Posted December 14, 2009

By Steven Reinberg
HealthDay Reporter
MONDAY, Dec. 14 (HealthDay News) -- milk thistle, appears to reduce liver damage resulting from chemotherapy, a new study finds.


Chemo drugs often cause liver damage, making it necessary to lower the dose or suspend treatment until the inflammation subsides. These interruptions in therapy can make treatment less effective, the researchers said.
"We found that milk thistle, compared to placebo, was more effective in reducing inflammation," said lead researcher Dr. Kara Kelly, from New York-Presbyterian Hospital/Columbia University Medical Center's Herbert Irving Comprehensive Cancer Center in New York City.
"If these results are confirmed, milk thistle may allow us to treat liver inflammation or prevent it from occurring, which will allow better delivery of chemotherapy drugs," she added.
The report is published in the Dec. 14 online edition of Cancer.
Milk thistle, a longtime folk remedy, is often recommended to treat liver damage and mushroom poisoning. No other treatment for liver toxicity exists, Kelly said.
For the study, Kelly's team randomly assigned 50 children undergoing chemotherapy for acute leukemia to receive milk thistle or a placebo for 28 days. All the children had liver inflammation at the start of the study.
Twenty-eight days later, the children who had received milk thistle had improved liver enzymes, compared with the children who received a placebo, the researchers said.
The milk thistle group had significantly lower levels of one enzyme in particular, AST, and a trend towards lower levels of another enzyme called ALT, Kelly's group found.
In addition, milk thistle appeared to help patients tolerate higher doses of chemotherapy. Sixty-one percent of the children receiving milk thistle needed dose reductions, compared with 72 percent of the children receiving placebo, but this difference is not significant, the researchers noted.
Related lab experiments showed the herb did not lessen the effectiveness of the chemotherapy drugs, and Kelly thinks milk thistle might reduce liver inflammation for patients with other cancers who are taking other types of chemotherapy as well. Further research is needed, she said, to determine the appropriate dose and duration of milk thistle therapy.
Her team also hopes to evaluate the herb's ability to prevent chemo-induced liver inflammation.
Still, some experts remain unconvinced about the herb's value in cancer treatment Dr. Julio C. Barredo, director of pediatric hematology-oncology at the University of Miami Miller School of Medicine, said that the study's small size, the low doses of milk thistle used and the short time frame of the study make the findings inconclusive.
Also, there was no difference in the delay of treatment in either group, he said.
"Improvement in one liver enzyme did not lead to patients who received the drug being delayed less than patients who received placebo in getting their chemotherapy," Barredo said.
"I don't think that you could recommend that people go and take this supplement when they are taking chemotherapy from the results of this study," Barredo said. "Maybe a larger study, using a higher dose is warranted."
Liver inflammation from chemotherapy usually abates when treatment stops or doses get reduced, Barredo added.




Med Hypotheses. 2010 Jan 18. [Epub ahead of print]
Practical strategies for suppressing hypoxia-inducible factor activity in cancer therapy.

McCarty MF, Barroso-Aranda J, Contreras F.
Oasis of Hope Hospital, Paseo Playas 19, Playas de Tijuana, Tijuana, B.C. 22504, Mexico.
The utility of anti-angiogenic strategies for cancer control is strongly compromised by hypoxia-driven phenotypic changes in cancer cells, which make cancer cells more invasive and more prone to give rise to metastases. A key mediator of this phenotypic shift is the transcription factor hypoxia-inducible factor-1 (HIF-1), which acts directly and indirectly to promote the epidermal-mesenchymal transition, boost cancer invasiveness, increase production of angiogenic factors, and induce chemoresistance. In some cancers, HIF-1 activity is constitutively elevated even in aerobic environments, making the cancer harder to treat and control. Practical strategies for suppressing HIF-1 activation may include the following: inhibiting NF-kappaB activation with salicylic acid and/or silibinin, which should decrease transcription of the HIF-1alpha gene; suppressing translation of HIF-1alpha mRNA with drugs that inhibit mTOR or topoisomerase I; supporting the effective activity of prolyl hydroxylases - which promote proteasomal degradation of HIF-1alpha under aerobic conditions - with antioxidant measures, alpha-ketoglutarate, and possibly dichloroacetate; promoting the O(2)-independent proteasomal degradation of HIF-1alpha with agents that inhibit the chaperone protein Hsp90; and blocking HIF-1 binding to its DNA response elements with anthracyclines. The utility of various combinations of these strategies should be tested in cancer cell cultures and rodent xenograft models; initial efforts in this regard have yielded encouraging results. Comprehensive strategies for suppressing HIF-1 activity can be expected to complement the efficacy of cancer chemotherapy and of effective anti-angiogenic regimens. Copyright © 2010 Elsevier Ltd. All rights reserved.

PMID: 20089365 [PubMed - as supplied by publisher]




www.raysahelian.com/silibinin.html
Silibinin is a flavonolignan found in certain herbs, particularly milk thistle

Acta Pharmacol Sin. 2009 Aug;30(8):1162-8. Epub 2009 Jul 6.
Silibinin inhibits prostate cancer invasion, motility and migration by suppressing vimentin and MMP-2 expression.

Wu KJ, Zeng J, Zhu GD, Zhang LL, Zhang D, Li L, Fan JH, Wang XY, He DL.
Department of Urology, First Affiliated Hospital of Medical School, Xi'an Jiaotong University, Xi'an 710061, China.
AIM: Silibinin is known to exert growth inhibition and cell death together with cell cycle arrest and apoptosis in human prostate cancer cells. Whether silibinin could inhibit the invasion, motility and migration of prostate cancer cells remains largely unknown. This study was designed to evaluate this efficacy and possible mechanisms using a novel highly bone metastatic ARCaP(M) cell model. METHODS: Four prostate cancer cell lines, LNCaP, PC-3, DU145, and ARCaP(M), were used in this study. These cells were treated with increasing concentrations of silibinin (50, 100, and 200 micromol/L) for different periods of time. After treatment, cell viabilities of four prostate cancer cells were compared by MTT assay. Alterations of ARCaP(M) cell invasion, motility and migration were assessed by cell invasion, motility and wound healing assays. The changes of vimentin expression were observed by Western blotting and immunofluorescence staining, and the expression of MMP-2, MMP-9, and uPA was analyzed by reverse transcription-polymerase chain reaction (RT-PCR). RESULTS: ARCaP(M) cells showed less sensitivity to the growth inhibition of pharmacological doses of silibinin than LNCaP, PC-3, and DU145 cells. However, silibinin exerted significant dose- and time-dependent inhibitory effects on the invasion, motility and migration of ARCaP(M) cells. Furthermore, the expression of vimentin and MMP-2, but not MMP-9 or uPA, was down-regulated in a dose- and time-dependent manner after treatment of silibinin. CONCLUSION: This study shows that silibinin could inhibit the invasion, motility and migration of ARCaP(M) cells via down-regulation of vimentin and MMP-2 and therefore may be a promising agent against prostate cancer bone metastasis.



Clin Cancer Res. 2008 Dec 1;14(23):7773-80.
Silibinin inhibits established prostate tumor growth, progression, invasion, and metastasis and suppresses tumor angiogenesis and epithelial-mesenchymal transition in transgenic adenocarcinoma of the mouse prostate model mice.

Singh RP, Raina K, Sharma G, Agarwal R.
Department of Pharmaceutical Sciences, School of Pharmacy, University of Colorado Denver, Denver, Colorado 80262, USA.
Comment in:
PURPOSE: The chronic nature of prostate cancer growth and progression leading to metastasis provides a large window for intervention. Herein, for the first time, we investigated the effect and associated mechanisms of silibinin phosphatidylcholine (silybin-phytosome) on established prostate tumors in transgenic adenocarcinoma of the mouse prostate (TRAMP) model. EXPERIMENTAL DESIGN: Twenty-week-old TRAMP male mice having palpable prostate tumor were fed with control or 0.5% and 1%, w/w, silybin-phytosome diets for 11 weeks and then sacrificed. RESULTS: Dietary silibinin inhibited the growth of prostate tumors (up to 60%, P < 0.001) and suppressed tumor progression from prostatic intraepithelial neoplasia to differentiated adenocarcinoma and poorly differentiated adenocarcinoma, with a complete absence of poorly differentiated adenocarcinoma at higher doses. It also inhibited the incidence of tumor invasion of seminal vesicle (up to 81%, P < 0.001) with complete absence of distant metastasis. Silibinin moderately inhibited tumor cell proliferation and induced apoptosis, but strongly suppressed tumor microvessel density (up to 60%, P < 0.001), vascular endothelial growth factor, and vascular endothelial growth factor receptor-2 expression. Antibody array analysis of plasma showed a decrease in the circulatory levels of vascular endothelial growth factor and basic fibroblast growth factor. Decreased levels of matrix metalloproteinases (MMP), snail-1, and vimentin, and an increased level of E-cadherin were also observed, indicating the anti-epithelial-mesenchymal transition effect of silibinin in tumors. CONCLUSIONS: Overall, silibinin treatment of TRAMP mice bearing prostate tumor inhibited tumor growth, progression, local invasion, and distant metastasis involving suppression of tumor angiogenesis and epithelial-mesenchymal transition. These findings would have greater relevance for the ongoing phase II clinical trial with silibinin-phytosome in prostate cancer patients.

PMID: 19047104 [PubMed - indexed for MEDLINE]



Acta Pharmacol Sin. 2009 Aug;30(8):1162-8. Epub 2009 Jul 6.
Silibinin inhibits prostate cancer invasion, motility and migration by suppressing vimentin and MMP-2 expression.

Wu KJ, Zeng J, Zhu GD, Zhang LL, Zhang D, Li L, Fan JH, Wang XY, He DL.
Department of Urology, First Affiliated Hospital of Medical School, Xi'an Jiaotong University, Xi'an 710061, China.
AIM: Silibinin is known to exert growth inhibition and cell death together with cell cycle arrest and apoptosis in human prostate cancer cells. Whether silibinin could inhibit the invasion, motility and migration of prostate cancer cells remains largely unknown. This study was designed to evaluate this efficacy and possible mechanisms using a novel highly bone metastatic ARCaP(M) cell model. METHODS: Four prostate cancer cell lines, LNCaP, PC-3, DU145, and ARCaP(M), were used in this study. These cells were treated with increasing concentrations of silibinin (50, 100, and 200 micromol/L) for different periods of time. After treatment, cell viabilities of four prostate cancer cells were compared by MTT assay. Alterations of ARCaP(M) cell invasion, motility and migration were assessed by cell invasion, motility and wound healing assays. The changes of vimentin expression were observed by Western blotting and immunofluorescence staining, and the expression of MMP-2, MMP-9, and uPA was analyzed by reverse transcription-polymerase chain reaction (RT-PCR). RESULTS: ARCaP(M) cells showed less sensitivity to the growth inhibition of pharmacological doses of silibinin than LNCaP, PC-3, and DU145 cells. However, silibinin exerted significant dose- and time-dependent inhibitory effects on the invasion, motility and migration of ARCaP(M) cells. Furthermore, the expression of vimentin and MMP-2, but not MMP-9 or uPA, was down-regulated in a dose- and time-dependent manner after treatment of silibinin. CONCLUSION: This study shows that silibinin could inhibit the invasion, motility and migration of ARCaP(M) cells via down-regulation of vimentin and MMP-2 and therefore may be a promising agent against prostate cancer bone metastasis.

PMID: 19578386 [PubMed - indexed for MEDLINE]




Am J Transl Res. 2009 Jan 1;1(1):80-6.
Silibinin suppresses CD44 expression in prostate cancer cells.

Handorean AM, Yang K, Robbins EW, Flaig TW, Iczkowski KA.
Prostate cancer (PCa), like most human cancers, features dysregulated CD44 expression. Expression of CD44 standard (CD44s), present in benign epithelium, is lost in PCa while pro-invasive splice variant isoform CD44v7-10 is overexpressed. The role of CD44 in silibinin's anti-growth effects was uncertain. To assess silibinin's effects on CD44 promoter activity, PC-3M PCa cells were transfected with luciferase-CD44 promoter construct 24 h prior to 25-200 muM silibinin treatment for 48 h. Also, cells' expression of CD44 RNA (by qRT-PCR) and protein (Western blot analysis) was studied. Silibinin was further tested preoperatively on a pilot cohort of 6 men with PCa compared with 7 matched placebo-treated men, with immunostaining for CD44v7-10 in their prostates. In PC-3M cells, silibinin dose-dependently inhibited CD44 promoter activity up to 87%, caused a 90% inhibition of total CD44 and 70% decrease in CD44v7-10 RNA, and at the protein level, decreased total CD44 at 100-200 muM dose and decreased CD44v7-10 after 3 days. Silibinin decreased adhesion to hyaluronan and fibronectin. Silibinin at 100-200 muM inhibited Egr-1, a regulator of CD44 promoter activity. Men treated with silibinin did not differ in tissue CD44v7-10 expression. In conclusion, CD44 inhibition is one mechanism by which silibinin reduces PCa tumorigenicity.

PMID: 19966941 [PubMed - in process]



Biochem Biophys Res Commun. 2009 Dec 4;390(1):71-6. Epub 2009 Sep 22.
Silibinin inhibits expression of HIF-1alpha through suppression of protein translation in prostate cancer cells.

Jung HJ, Park JW, Lee JS, Lee SR, Jang BC, Suh SI, Suh MH, Baek WK.
Chronic Disease Research Center, School of Medicine, Keimyung University, Daegu 700-712, Republic of Korea.
Silibinin is a polyphenolic flavonoid isolated from the milk thistle (Silybum marianum) and is reported to exhibit anticancer properties. Recently, it has been reported that silibinin inhibits hypoxia-inducible factor-1alpha (HIF-1alpha) expression in cancer cells. However, the precise mechanism by which silibinin decreases HIF-1 expression is not fully understood. In this study, silibinin inhibited basal and hypoxia induced expression levels of HIF-1alpha protein in LNCaP and PC-3 prostate cancer cells, while the rate of HIF-1alpha protein degradation and mRNA levels were not affected. We found that the decrease in HIF-1 protein by silibinin correlated with suppression of de novo synthesis of HIF-1alpha protein. Silibinin inhibited global protein synthesis coincided with reduction of eIF4F complex formation and induction of phosphorylation of the translation initiation factor 2alpha (eIF-2alpha) which can cause inhibition of general protein synthesis. These results suggest that silibinin's activity to inhibit HIF-1alpha protein expression is associated with the suppression of global protein translation.

PMID: 19778521 [PubMed - indexed for MEDLINE]



Cancer Res. 2008 Aug 15;68(16):6822-30.
Stage-specific inhibitory effects and associated mechanisms of silibinin on tumor progression and metastasis in transgenic adenocarcinoma of the mouse prostate model.

Raina K, Rajamanickam S, Singh RP, Deep G, Chittezhath M, Agarwal R.
Department of Pharmaceutical Sciences, School of Pharmacy, University of Colorado Denver, Denver, Colorado 80262, USA.

FREE TEXT


Herein, using transgenic adenocarcinoma of the mouse prostate (TRAMP) model, we assessed the "stage-specific" efficacy of silibinin feeding against prostate cancer (PCa) initiation, progression, angiogenesis and metastasis, and associated molecular events involved in silibinin effects during these stages. Male TRAMP mice starting at ages 4, 12, 20, and 30 weeks of age were fed with control or 1% silibinin-supplemented diet for 8 to 15 weeks in stage-specific manners. At the end of studies, silibinin-fed mice showed less severe prostatic lesions compared with positive controls. During early stages of prostate tumor development, silibinin mediated its efficacy mostly via antiproliferative mechanisms. Feeding of silibinin to animals burdened with higher stages of prostate tumor significantly decreased tumor grade via antiproliferative effect, and inhibition of angiogenesis as evidenced by decreased expressions of platelet endothelial cell adhesion molecule-1/CD-31, vascular endothelial growth factor, and associated receptor, vascular endothelial growth factor R2, hypoxia-inducible factor-1alpha, and inducible nitric oxide synthase. Metastasis to distant organs was decreased in silibinin-fed mice, which was associated with a decreased expression of matrix metalloproteinases, mesenchymal markers snail-1, and fibronectin in the prostatic tissue and retention of epithelial characteristics. Together, these findings are both novel and highly significant in establishing the dual efficacy of silibinin where it inhibits progression of primary prostatic tumor and also shows protective efficacy against angiogenesis and late stage metastasis. These effects of silibinin could have potential implications to improve the morbidity and survival in PCa patients.

PMID: 18701508 [PubMed - indexed for MEDLINE]




Neurochem Res. 2009 Aug;34(8):1479-90. Epub 2009 Mar 5.
Silibinin inhibits glioma cell proliferation via Ca2+/ROS/MAPK-dependent mechanism in vitro and glioma tumor growth in vivo.

Kim KW, Choi CH, Kim TH, Kwon CH, Woo JS, Kim YK.
Department of Neurosurgery, College of Medicine, Pusan National University, Pusan 602-739, Korea.
Anticancer activity of silibinin, a flavonoid, has been demonstrated in various cancer cell types. However, the underlying mechanism and in vivo efficacy in glioma were not elucidated. The present study was undertaken to determine the effect of silibinin on glioma cell proliferation in vitro and to examine whether silibinin inhibits tumor growth in vivo. Silibinin resulted in inhibition of proliferation in a dose- and time-dependent manner, which was largely attributed to cell death. Silibinin induced a transient increase in intracellular Ca2+ followed by an increase in reactive oxygen species (ROS) generation. The silibinin-induced cell death was prevented by EGTA, calpain inhibitor and antioxidants (N-acetylcysteine and Trolox). Western blot analysis showed that silibinin also induced ROS-dependent activation of extracellular signal-regulated kinase, p38 kinase, and c-Jun N-terminal kinase. Inhibitors of these kinases prevented the silibinin-induced cell death. Silibinin caused caspase activation and the silibinin-induced cell death was prevented by caspase inhibitors. Glioma cell migration was also decreased by silibinin treatment. Oral administration of silibinin in animals with subcutaneous U87MG glioma cells reduced tumor volume. Subsequent tumor tissue analysis showed a decrease in Ki-67 positive cells, an increase in TUNEL-positive cells, and caspase activation. These results indicate that silibinin induces a caspase-dependent cell death via Ca2+/ROS/MAPK-mediated pathway in vitro and inhibits glioma growth in vivo. These data suggest that silibinin may serve as a potential therapeutic agent for malignant human gliomas.

PMID: 19263218 [PubMed - indexed for MEDLINE]






J Pharmacol Exp Ther. 2009 Nov 24. [Epub ahead of print]
TWO FLAVONOLIGNANS FROM MILK THISTLE (SILYBUM MARIANUM) INHIBIT CYP2C9-MEDIATED WARFARIN METABOLISM AT CLINICALLY ACHIEVABLE CONCENTRATIONS.

Brantley SJ, Oberlies NH, Kroll DJ, Paine MF.
1 The University of North Carolina at Chapel Hill;
Milk thistle (Silybum marianum) is a popular herbal product used for hepatoprotection and chemoprevention. Two commercially available formulations are the crude extract, silymarin, and the semi-purified product, silibinin. Silymarin consists of at least seven flavonolignans, of which the most prevalent are the diastereoisomers silybin A and silybin B; silibinin consists only of silybin A and silybin B. Based on a recent clinical study showing an interaction between a silymarin product and the CYP2C9 substrate losartan, the CYP2C9 inhibition properties of silybin A and silybin B, along with corresponding regioisomers, isosilybin A and isosilybin B, were evaluated using human liver microsomes (HLM), recombinant CYP2C9 (rCYP2C9) enzymes, and the clinically relevant probe, (S)-warfarin. Silybin B was the most potent inhibitor in HLM, followed by silybin A, isosilybin B, and isosilybin A (IC(50) values of 8.2, 18, 74, and >100 muM, respectively). Next, silybin A and silybin B were selected for further characterization. As with HLM, silybin B was more potent than silybin A towards rCYP2C9*1 (6.7 vs. 12 muM), rCYP2C9*2 (9.3 vs. 19 muM), and rCYP2C9*3 (2.4 vs. 9.3 muM). Using a matrix of 5 substrate (1-15 muM) and 6 inhibitor (1-80 muM) concentrations, both diastereoisomers inhibited (S)-warfarin 7-hydroxylation in HLM in a mostly competitive manner (K(i) of 4.8 and 10 muM for silybin B and silybin A, respectively). These observations, combined with the high systemic silibinin concentrations (>5-75 muM) achieved in a recent phase I study involving prostate cancer patients, prompt clinical evaluation of a potential warfarin-milk thistle interaction.

PMID: 19934397 [PubMed - as supplied by publisher]




Altern Med Rev. 2005 Sep;10(3):193-203.
A review of the bioavailability and clinical efficacy of milk thistle phytosome: a silybin-phosphatidylcholine complex (Siliphos).

Kidd P, Head K.
University of California, Berkeley, USA. dockidd@dockidd.com
Certain of the water-soluble flavonoid molecules can be converted into lipid-compatible molecular complexes, aptly called phytosomes. Phytosomes are better able to transition from a hydrophilic environment into the lipid-friendly environment of the outer cell membrane, and from there into the cell, finally reaching the blood. The fruit of the milk thistle plant (Silybum marianum, Family Asteraceae) contains flavonoids that are proven liver protectants. The standardized extract known as silymarin contains three flavonoids of the flavonol subclass. Silybin predominates, followed by silydianin and silychristin. Although silybin is the most potent of the flavonoids in milk thistle, similar to other flavonoids it is not well-absorbed. Silybin-phosphatidylcholine complexed as a phytosome provides significant liver protection and enhanced bioavailability over conventional silymarin.

PMID: 16164374 [PubMed - indexed for MEDLINE]



Carcinogenesis. 2007 Jul;28(7):1463-70. Epub 2007 Mar 6.
Silibinin inhibits constitutive activation of Stat3, and causes caspase activation and apoptotic death of human prostate carcinoma DU145 cells.

FULL TEXT





Agarwal C, Tyagi A, Kaur M, Agarwal R.
Department of Pharmaceutical Sciences, School of Pharmacy, University of Colorado Cancer Center, University of Colorado Health Sciences Center, Denver, CO 80262, USA.
Transcription factor signal transducer and activator of transcription (Stat)-3 is activated constitutively in prostate cancer (PCA) suggesting that its disruption could be an effective approach to control this malignancy. Here we assessed whether silibinin, a flavanone from Silybum marianum with proven anticancer efficacy in various cancer models, inhibits Stat3 activation in DU145 cells, and if it does, what is the biological fate of the cells? At 50 muM or higher concentrations for 24 or 48 h, silibinin concentration dependently reduced constitutive Stat3 phosphorylation at Tyr705 and Ser727 residues under both serum and serum-starved conditions. Constitutively active Stat3-DNA binding was also inhibited concentration dependently by silibinin; however, apoptotic death together with caspase and poly(ADP-ribose) polymerase (PARP) cleavage was observed by silibinin only under serum-starved conditions suggesting that additional survival pathways are active under serum conditions. In other studies, cells were treated with various specific pharmacological inhibitors where phosphorylation of Stat3 was not reduced by epidermal growth factor receptor and Mitogen activated protein/extracellular signal regulate kinase kinase (MEK1/2) inhibitors, suggesting lack of significant roles of these in Stat3 activation in DU145 cells. Janus kinase (JAK)-1 and JAK2 inhibitors strongly reduced Stat3 phosphorylation but did not result in apoptotic cell death. Interestingly, JAK1 inhibitor only in combination with silibinin resulted in a complete reduction in Stat3 phosphorylation at Tyr705, activated caspase-9 and caspase-3, and caused strong PARP cleavage and apoptotic death of DU145 cells. Given a critical role of Stat3 activation in PCA, our results showed that silibinin inhibits constitutively active Stat3 and induces apoptosis in DU145 cells, and thus might have potential significance in therapeutic intervention of this deadly malignancy.

PMID: 17341659 [PubMed - indexed for MEDLINE]

Quote:
The results of the present study might have important implications in altering the outcome of PCA in humans because of high bioavailability of silibinin in human plasma, as in our ongoing clinical trial (20), we were able to achieve nearly 70 uM concentration of circulating silibinin in humans when it was given to patients in the form of silibinin phytosome.


20. Flaig,T.W. et al. (2007) A phase I and pharmacokinetic study of silybinphytosome in prostate cancer patients. Investig. New Drugs, 25, 139–146 In press.





Altern Med Rev. 2009 Sep;14(3):226-46.
Bioavailability and activity of phytosome complexes from botanical polyphenols: the silymarin, curcumin, green tea, and grape seed extracts.

Kidd PM.
Cell biology, University of California, Berkeley, USA. dockidd@dockidd.com
Plant-derived polyphenols are increasingly receiving attention as dietary supplements for the homeostatic management of inflammation, to support detoxication, and for anticancer, weight loss, and other benefits. Their pro-homeostatic effects on genes, transcription factors, enzymes, and cell signaling pathways are being intensively explored, but the poor bioavailability of some polyphenols likely contributes to poor clinical trial outcomes. This review covers four polyphenol preparations with poor bioavailability and their complexation into phytosomes to bypass this problem. Silybin and the other silymarin flavonolignans from milk thistle conserve tissue glutathione, are liver-protective, and have anticancer potential. Curcumin and its related diphenolic curcuminoids have potent antioxidant, anti-inflammatory, and anti-carcinogenic properties. The green tea flavan-3-ol catechins have antioxidant, anti-inflammatory, cardio- and neuro-protective effects, and anti-carcinogenic benefits, with fat oxidation effects coupled to weight loss. The complex grape seed proanthocyanidin mix (including catechin and epicatechin monomers and oligomers) counters oxidative stress and protects the circulatory system. For each of these preparations, conversion into phytosomes has improved efficacy without compromising safety. The phytosome technology creates intermolecular bonding between individual polyphenol molecules and one or more molecules of the phospholipid, phosphatidylcholine (PC). Molecular imaging suggests that PC molecule(s) enwrap each polyphenol; upon oral intake the amphipathic PC molecules likely usher the polyphenol through the intestinal epithelial cell outer membrane, subsequently accessing the bloodstream. PC itself has proven clinical efficacy that contributes to phytosome in vivo actions. As a molecular delivery vehicle, phytosome technology substantially improves the clinical applicabilities of polyphenols and other poorly absorbed plant medicinals.

PMID: 19803548 [PubMed - indexed for MEDLINE]



A phytosome formulation of milk thistle for sale: HERE



Wikipedia exploration
http://en.wikipedia.org/wiki/Silibinin




Free Radic Res. 2010 Jan;44(1):90-100.
Silibinin induces protective superoxide generation in human breast cancer MCF-7 cells.

Wang HJ, Jiang YY, Wei XF, Huang H, Tashiro S, Onodera S, Ikejima T.
China-Japan Research Institute of Medical and Pharmaceutical Sciences, Shenyang Pharmaceutical University, Shenyang 110016, PR China.
The pharmacological activity of polyphenolic silibinin from milk thistle (Silybum marianum) is primarily due to its antioxidant property. However, this study found that silibinin promoted sustained superoxide (O(2)(.-)) production that was specifically scavenged by exogenous superoxide dismutase (SOD) in MCF-7 cells, while the activity of endogenous SOD was not changed by silibinin. Previous work proved that silibinin induced MCF-7 cell apoptosis through mitochondrial pathway and this study further proved that O(2)(.-) generation induced by silibinin was also related to mitochondria. It was found that respiratory chain complexes I, II and III were all involved in silibinin-induced O(2)(.-) generation. Moreover, it was found that silibinin-induced O(2)(.-) had protective effect, as exogenous SOD markedly enhanced silibinin-induced apoptosis.

PMID: 19968587 [PubMed - in process]
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Old 01-26-2010, 02:32 PM   #2
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Re: Milk thistle

Wow, thanks for this excellent article on milk thistle and chemo. I know milk thistle has been used for quite some time to help repair the liver when it has been damaged by drugs or alcohol. I think milk thistle has been most predominantly used for those with cirrhosis of the liver. But it definitely makes sense to use it after chemo treatment to help reduce and repair liver damage done by the treatments. Definitely something to run by your doctor, because it does have several drug interactions, but it's definitely a good supplement to look into.
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Old 01-26-2010, 02:58 PM   #3
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Thumbs up Re: Milk thistle

In 2002 I took Milk Thistle when I had to undergo treatment for a major invasion of tumors in my liver. My friend who is a recovered alcoholic suggested this and my med onc decided it was OK to take it.

I was careful to take a trusted brand of "Standardized" Milk Thistle. I did take it for a couple of years. In summer of 2002 I was pronounced with a complete remission and have had nothing come back in my liver since then.

There were no side effects or symptoms that I could notice with the Milk Thistle.
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Old 01-26-2010, 03:27 PM   #4
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Wink Re: Milk thistle

I have taken milk thistle prescribed by my naturopathic physician every day for 11 years. I haven't had liver mets. I haven't had an abnormal liver function on my blood tests since I started taking it. I am planning to take it forever.
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Old 01-26-2010, 05:08 PM   #5
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Re: Milk thistle

Hmmm. Glad you folks commented. Just added a bunch of newer abstracts to this. Looks like Steph was on to something. What brand did you use? The Health day article is still significant in that it was a human trial demonstrating it was helpful/complimentary during a conventional therapy. Research may be more advanced in prostate cancer. But the mechanisms discussed don't seem PCa specific. It looks like it has shown efficacy in many cancers, with many mechanisms identified. Pretty good for something known to actually reduce toxicity. The CD44 (cancer stem cell) abstract sure looks fundamental. As mentioned, perhaps some med interactions possible...blood thinners and BP meds look questionable. And looks like different versions may be more "bioavailable". Milk thistle salad anyone?
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Old 02-06-2010, 09:14 PM   #6
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Re: Milk thistle

Anticancer Res. 2010 Jan;30(1):79-85.
Effects of silybinin on the pharmacokinetics of tamoxifen and its active metabolite, 4-hydroxytamoxifen in rats.

Kim CS, Choi SJ, Park CY, Li C, Choi JS.
College of Pharmacy, Chosun University, Dong-Gu, Gwangju 501-759, Republic of Korea. jsachoi@chosun.ac.kr.
The effects of silybinin, an antioxidant, on the pharmacokinetics of tamoxifen and its metabolite, 4-hydroxytamoxifen, were investigated in rats. A single dose of tamoxifen was administered intravenously (2 mg/kg) and orally (10 mg/kg) without or with silybinin (0.5, 2.5 and 10 mg/kg) to rats. Silybinin significantly altered the pharmacokinetics of orally administered tamoxifen. Compared to those in the oral control group (given tamoxifen alone), the area under the plasma concentration-time curve (AUC(0-infinity)) and the peak plasma concentration (C(max)) of tamoxifen were significantly (p<0.05 for 2.5 mg/kg, p<0.01 for 10 mg/kg) increased by 40.2-71.3% and 45.2-78.6%, respectively, with silybinin. Consequently, the absolute bioavailability (AB) of tamoxifen in the presence of silybinin (2.5 and 10 mg/kg) was 31.1-38.1%, which was significantly enhanced (p<0.05) compared to that in the oral control group (22.2%). Moreover, the relative bioavailability (RB) of tamoxifen was 1.40- to 1.72-fold greater than that in the control group. Silybinin (10 mg/kg) significantly increased the AUC(0-infinity) (p<0.05, 40.0%) of 4-hydroxytamoxifen, but the metabolite-parent ratio (MR) of 4-hydroxytamoxifen was significantly altered (p<0.05 for 10 mg/kg), implying that the formation of 4-hydroxytamoxifen was considerably affected by silybinin. The enhanced bioavailability of tamoxifen by silybinin might be due to the promotion of intestinal absorption in the small intestine and the reduction of first-pass metabolism of tamoxifen in the small intestine and in the liver. If these results are confirmed in clinical trials, the tamoxifen dosage should be adjusted when tamoxifen is administered with silybinin or silybinin-containing dietary supplements.

PMID: 20150620 [PubMed - in process]





Cancer Res. 2008 Mar 15;68(6):2043-50.
Silibinin inhibits colorectal cancer growth by inhibiting tumor cell proliferation and angiogenesis.

Singh RP, Gu M, Agarwal R.
Department of Pharmaceutical Sciences, School of Pharmacy, University of Colorado Denver, CO 80262, USA.
Herein, for the first time, we investigated in vivo efficacy and associated molecular biomarkers and mechanisms of a chemopreventive agent, silibinin, against human colorectal carcinoma (CRC) HT29 xenograft growth. Nude mice were implanted with HT29 cells and fed with vehicle (carboxymethyl cellulose or phosphatidylcholine) or 200 mg/kg/d dose of silibinin or 100 and 200 mg/kg/d doses of silybin-phytosome (5 days per week) for 32 days. Silibinin inhibited tumor growth that accounted for 48% (P = 0.002) decrease in tumor volume and 42% (P = 0.012) decrease in tumor weight at the end of the experiment without any adverse health effect. A stronger antitumor efficacy was observed with silybin-phytosome preparation. Silibinin decreased proliferation index by 40% (P < 0.001), increased apoptotic index by approximately 2-fold (P = 0.001), and reduced microvessel density by 36% (P = 0.001) in tumors. Antiproliferative and proapoptotic effects of silibinin were associated with down-regulation of extracellular signal-regulated kinase 1/2 (ERK1/2) and Akt phosphorylation as well as cyclin D1 expression. Antiangiogenic effect of silibinin was coupled with a strong decrease in inducible nitric oxide synthase (NOS) and NOS3, cyclooxygenase-1 (COX-1) and COX-2, and hypoxia-inducing factor-1 alpha (HIF-1 alpha) and vascular endothelial growth factor (VEGF). These findings suggest in vivo antitumor efficacy of silibinin against CRC involving its antiproliferative, proapoptotic, and antiangiogenic activities. The inhibition of ERK1/2 and Akt signaling may account for antiproliferative and proapoptotic effects, whereas down-regulation of NOS, COX, HIF-1 alpha, and VEGF expression could lead to antiangiogenic effect of silibinin against CRC. Overall, potential use of silibinin against human CRC could be suggested.

PMID: 18339887 [PubMed - indexed for MEDLINE]





Clin Cancer Res. 2008 Dec 1;14(23):7773-80.
Silibinin inhibits established prostate tumor growth, progression, invasion, and metastasis and suppresses tumor angiogenesis and epithelial-mesenchymal transition in transgenic adenocarcinoma of the mouse prostate model mice.

Singh RP, Raina K, Sharma G, Agarwal R.
Department of Pharmaceutical Sciences, School of Pharmacy, University of Colorado Denver, Denver, Colorado 80262, USA.
Comment in:
PURPOSE: The chronic nature of prostate cancer growth and progression leading to metastasis provides a large window for intervention. Herein, for the first time, we investigated the effect and associated mechanisms of silibinin phosphatidylcholine (silybin-phytosome) on established prostate tumors in transgenic adenocarcinoma of the mouse prostate (TRAMP) model. EXPERIMENTAL DESIGN: Twenty-week-old TRAMP male mice having palpable prostate tumor were fed with control or 0.5% and 1%, w/w, silybin-phytosome diets for 11 weeks and then sacrificed. RESULTS:Dietary silibinin inhibited the growth of prostate tumors (up to 60%, P < 0.001) and suppressed tumor progression from prostatic intraepithelial neoplasia to differentiated adenocarcinoma and poorly differentiated adenocarcinoma, with a complete absence of poorly differentiated adenocarcinoma at higher doses. It also inhibited the incidence of tumor invasion of seminal vesicle (up to 81%, P < 0.001) with complete absence of distant metastasis. Silibinin moderately inhibited tumor cell proliferation and induced apoptosis, but strongly suppressed tumor microvessel density (up to 60%, P < 0.001), vascular endothelial growth factor, and vascular endothelial growth factor receptor-2 expression. Antibody array analysis of plasma showed a decrease in the circulatory levels of vascular endothelial growth factor and basic fibroblast growth factor. Decreased levels of matrix metalloproteinases (MMP), snail-1, and vimentin, and an increased level of E-cadherin were also observed, indicating the anti-epithelial-mesenchymal transition effect of silibinin in tumors. CONCLUSIONS: Overall, silibinin treatment of TRAMP mice bearing prostate tumor inhibited tumor growth, progression, local invasion, and distant metastasis involving suppression of tumor angiogenesis and epithelial-mesenchymal transition. These findings would have greater relevance for the ongoing phase II clinical trial with silibinin-phytosome in prostate cancer patients.

PMID: 19047104 [PubMed - indexed for MEDLINE]
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Old 10-27-2011, 03:05 AM   #7
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Re: Milk thistle

Steph
What dosage of milk thistle did you take? My very poor liver function tests are precluding me from a THERESA TDM-1 trial I would otherwise be eligible for. Exquisitely bad timing on my part-my liver fuction would have been OK a couple of months ago.Unfortunately it is the tumour growth rather than the chemo I think that is causing the problem.
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4/2011
Tyk+Herc+Femara
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Liver and bone mets prog.Abraxane continue Herceptin,Tykerb,Femara and Zometa
8/2011
Probable liver progression and increased neuropathy. Xeloda with Tyk+Herc. Zometa 6 weekly.
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Old 10-27-2011, 02:40 PM   #8
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Wink Re: Milk thistle

I think a nutritionist or naturopathic physician can help with milk thistle doses.
Milk thistle is good. You may also want to consider eating more kale, beets, carrots, crucifious vegetables and danelion greens. Those who are familar with gobo (burdock root) might also want to consider eating that. I posted a link to information about these vegetables and the liver within the last 6 weeks. I probably posted it in the diet and nutrition thread.
Some supplements also contain those other things in addition to milk thistle.
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Old 10-28-2011, 04:54 AM   #9
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Re: Milk thistle

Thanks for the info Elaine and I'll visit the nutrition thread.
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5/2004 (R) 30mm bre gr3 infiltrating ductal ca 16/18nodes er (2+) pr (3+) HER2 (3+)
6/2004
6 cycles(FEC), Oct 40 rads, Tamoxifen
5/2006
oopherectomy, Arimedex
12/2006
liver mets largest 9cm
1/2007
Herceptin,
3/2007
Taxol + Herc
1/2008
Herc alone
4/2008
Multiple bone mets,Zometa
7/2008
Herc + Gemcitabine
8/2008
Herc+Navelbine/vinoralbine
10/2008
Herc+Carboplatin+Taxol
12/2008
Tykerb+Xeloda
2/2010
Herceptin + trial drug
5/2010
Herceptin+Tykerb
8/2010
Tykerb+Abraxane
9/2010
Abraxane
12/2010
Abraxane+Tyk+Herc
4/2011
Tyk+Herc+Femara
6/2011
Liver and bone mets prog.Abraxane continue Herceptin,Tykerb,Femara and Zometa
8/2011
Probable liver progression and increased neuropathy. Xeloda with Tyk+Herc. Zometa 6 weekly.
9/2011
Liver progression,TM +++. Cyclophosphamide and Methotrexate metro Herc Zometa
10/2011 liver mets prog.Herc, 3 Tykerb +2mg decodron daily,Zometa
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Old 11-03-2011, 08:46 AM   #10
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Re: Milk thistle

Milk thistle has nothing to do with milk...
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