A phase I and pharmacokinetic study of silybin-phytosome in prostate cancer patients

Flaig, Thomas W.; Gustafson, Daniel L.; Su, Lih-Jen; Zirrolli, Joseph A.; Crighton, Frances; Harrison, Gail Singer; Pierson, A. Scott; Agarwal, Rajesh; Glodé, L. Michael

doi:10.1007/s10637-006-9019-2

Cited by 281 publications

(236 citation statements)

References 19 publications

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“…Though intervention with silibinin was found to be ineffective in modulating the circulating levels of IGFBP-3, IGF-1 and pyrimidopurinone adduct of dexoguanosine, a marker for oxidative DNA damage; however it is worthy to note that high levels of silibinin were achieved in colorectal mucosa of the patients, which further supports the need of conducting more elaborate clinical trials for evaluating its efficacy as potential chemopreventive agent (Hoh et al, 2006). Our group has also recently completed a Phase-I clinical trial with silibinin in prostate cancer patients (Flaig et al, 2006). This trial was designed to assess the toxicity of high dose silybin-phytosome, a commercial preparation, and recommend a dose for phase II trial.…”

Section: Clinical Trials With Silibinin In Cancer Patientsmentioning

confidence: 87%

Silymarin and epithelial cancer chemoprevention: How close we are to bedside?

Kaur

Agarwal

2007

Toxicology and Applied Pharmacology

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Failure and high systemic toxicity of conventional cancer therapies have accelerated the focus on the search for newer agents, which could prevent and/or slow-down cancer growth and have more human acceptability by being less or non-toxic. Silymarin is one such agent, which has been extensively used since ages for the treatment of liver conditions, and thus has possibly the greatest patient acceptability. In recent years, increasing body of evidence has underscored the cancer preventive efficacy of silymarin in both in vitro and in vivo animal models of various epithelial cancers. Apart from chemopreventive effects, other noteworthy aspects of silymarin and its active constituent silibinin in cancer treatment include their capability to potentiate the efficacy of known chemotherapeutic drugs, as an inhibitor of multidrug resistance associated proteins, and as an adjunct to the cancer therapeutic drugs due to their organ-protective efficacy specifically liver, and immunostimulatory effects. Widespread use of silymarin for liver health in humans and commercial availability of its formulations with increased bioavailability, further underscore the necessity of carrying out controlled clinical trials with these agents in cancer patients. In this review, we will briefly discuss the outcomes of clinical trials being conducted by us and others in cancer patients to provide insight into the clinical relevance of the observed chemopreventive effects of these agents in various epithelial cancer models.

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Section: Clinical Trials With Silibinin In Cancer Patientsmentioning

confidence: 87%

Silymarin and epithelial cancer chemoprevention: How close we are to bedside?

Kaur

Agarwal

2007

Toxicology and Applied Pharmacology

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“…Many studies indicated that increased levels of MMP-2 or MMP-9 in the serum or tissue samples of prostate cancer patients are correlated with advanced stage (43,44). In vitro studies also showed the expression of MMP-2 and MMP-9 associate with high invasive and metastatic potential of prostate cancer cell lines (45)(46)(47)(48). Moreover, the expression of MMP-2, MMP-9 or TIMP-3 showed a 100% specificity for diagnoses of prostate cancer (49).…”

Section: Discussionmentioning

confidence: 99%

ADAM17 targets MMP-2 and MMP-9 via EGFR-MEK-ERK pathway activation to promote prostate cancer cell invasion

Xiao

Lin²,

Lin³

et al. 2011

Int J Oncol

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Abstract. ADAM17, also known as tumor necrosis factor-α converting enzyme (TACE), is involved in proteolytic ectodomain shedding of cell surface molecules and cytokines. Although aberrant expression of ADAM17 has been shown in various malignancies, the function of ADAM17 in prostate cancer has not been clarified. In the present study, we sought to elucidate whether ADAM17 contributes to prostate cancer cell invasion, as well as the mechanism involved in the process. The expression pattern of ADAM17 was investigated in human prostate cancer cells. The results showed that ADAM17 expression levels are correlated with the invasive ability of androgen-independent prostate cancer cell lines. Further, ADAM17 was overexpressed in cells showing high invasion characteristics, activation of the EGFR-MEK-ERK pathway, up-regulation of MMP-2, MMP-9, and an increased TGF-α release into the supernatant. However, AG1478, PD98059 and antibody against TGF-α deactivating the EGFR-MEK-ERK signaling pathway, abolished up-regulation of MMP-2, MMP-9 and prevented cell invasion. In addition, cells with knockdown of ADAM17 by siRNA exhibited low invasive ability, deactivated EGFR-MEK-ERK signaling pathway, reduced TGF-α released and down-regulation of MMP-2, MMP-9. However, these effects could be reversed by simultaneous addition of TGF-α. These data demonstrated that ADAM17 contributes to androgen-independent prostate cancer cell invasion by shedding of EGFR ligand TGF-α, which subsequently activates the EGFR-MEK-ERK signaling pathway, leading finally to overexpression of MMP-2 and MMP-9. This study suggests that the ADAM17 expression level may be a new predictive biomarker of invasion and metastasis of prostate cancer, and ADAM17 could provide a target for treating metastatic PCa. IntroductionProstate cancer (PCa) is one of the most common malignancies among Western males with an occurrence of approximately 192,280 new cases and 27,360 deaths in the US, in 2009 (1). The growth and maintenance of cancerous cells in the early stages of prostate cancer is androgen-dependent and therapy often involves androgen deprivation (2). In the later stages therapeutic alternatives are not available, as the tumor progresses from androgen-dependence to -independence. The lack of effective therapies for advanced PCa is related to a large extent to poor understanding of the molecular mechanisms underlying the progression of disease toward invasion and metastasis (3). Therefore, the identification of new predictive biomarkers, especially those that are indicative of invasiveness of the disease, which could serve as targets for establishing effectiveness of therapeutic and chemopreventive interventions, will improve clinical management of PCa (4).The ADAMs (a disintegrin and metalloproteinase) are members of the metzincin superfamily of Zn-dependent matrix metalloproteinases. They are transmembrane and secreted proteins with important roles in diverse biological functions, such as fertilization, adhesion, migration, proteolysis and signaling (5,6). Recent...

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“…The silybin phytosome complex (silybin plus phosphatidylcholine) has been coformulated with vitamin E (Realsil (RA); Istituto Biochimico Italiano, Lorenzini S.p.a., Italy). Pharmacokinetic analyses indicated that silybin phytosome bioavailability is much higher than silymarin bioavailability [17,18].…”

mentioning

confidence: 99%

Silybin combined with phosphatidylcholine and vitamin E in patients with nonalcoholic fatty liver disease: A randomized controlled trial

Loguercio

Andreone

Brisc

et al. 2012

Free Radical Biology and Medicine

213

147

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The only currently recommended treatment for nonalcoholic fatty liver disease (NAFLD) is lifestyle modification. Preliminary studies of silybin showed beneficial effects on liver function. Realsil (RA) comprises the silybin phytosome complex (silybin plus phosphatidylcholine) coformulated with vitamin E. We report on a multicenter, phase III, double-blind clinical trial to assess RA in patients with histologically documented NAFLD. Patients were randomized 1:1 to RA or placebo (P) orally twice daily for 12 months. Prespecified primary outcomes were improvement over time in clinical condition, normalization of liver enzyme plasma levels, and improvement of ultrasonographic liver steatosis, homeostatic model assessment (HOMA), and quality of life. Secondary outcomes were improvement in liver histologic score and/or decrease in NAFLD score without worsening of fibrosis and plasma changes in cytokines, ferritin, and liver fibrosis markers. We treated 179 patients with NAFLD; 36 were also HCV positive. Forty-one patients were prematurely withdrawn and 138 patients analyzed per protocol (69 per group). Baseline patient characteristics were generally well balanced between groups, except for steatosis, portal infiltration, and fibrosis. Adverse events (AEs) were generally transient and included diarrhea, dysgeusia, and pruritus; no serious AEs were recorded. Patients receiving RA but not P showed significant improvements in liver enzyme plasma levels, HOMA, and liver histology. Body mass index normalized in 15% of RA patients (2.1% with P). HCV-positive patients in the RA but not the P group showed improvements in fibrogenesis markers. This is the first study to systematically assess silybin in NAFLD patients. Treatment with RA but not P for 12 months was associated with Free

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A phase I and pharmacokinetic study of silybin-phytosome in prostate cancer patients

Cited by 281 publications

References 19 publications

Silymarin and epithelial cancer chemoprevention: How close we are to bedside?

Silymarin and epithelial cancer chemoprevention: How close we are to bedside?

ADAM17 targets MMP-2 and MMP-9 via EGFR-MEK-ERK pathway activation to promote prostate cancer cell invasion

Silybin combined with phosphatidylcholine and vitamin E in patients with nonalcoholic fatty liver disease: A randomized controlled trial

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