Pilot Study of Oral Silibinin, a Putative Chemopreventive Agent, in Colorectal Cancer Patients: Silibinin Levels in Plasma, Colorectum, and Liver and Their Pharmacodynamic Consequences

Abstract

Silibinin, a flavonolignan from milk thistle, has intestinal cancer chemopreventive efficacy in rodents. It is a strong antioxidant and modulates the insulin-like growth factor (IGF) system by increasing circulating levels of IGF-binding protein 3 (IGFBP-3) and decreasing levels of IGF-I.Here, the hypothesis was tested that administration of oral silibinin generates agent levels in human blood and colorectal and hepatic tissues consistent with pharmacologic activity. Patients with confirmed colorectal adenocarcinoma received silibinin formulated with phosphatidylcholine (silipide) at dosages of 360, 720, or 1,440 mg silibinin daily for 7 days. Blood and biopsy samples of normal and malignant colorectum or liver were obtained before dosing, and blood and colorectal or hepatic tissues were collected at resection surgery after the final silipide dose. Levels of silibinin were quantified by high-pressure liquid chromatography-UV, and plasma metabolites were identified by liquid chromatography-mass spectrometry. Blood levels of IGFBP-3, IGF-I, and the oxidative DNA damage pyrimidopurinone adduct of deoxyguanosine (M 1 dG) were determined. Repeated administration of silipide was safe and achieved levels of silibinin of 0.3 to 4 Amol/L in the plasma, 0.3 to 2.5 nmol/g tissue in the liver, and 20 to 141nmol/g tissue in colorectal tissue. Silibinin monoglucuronide, silibinin diglucuronide, silibinin monosulfate, and silibinin glucuronide sulfate were identified in the plasma. Intervention with silipide did not affect circulating levels of IGFBP-3, IGF-I, or M 1 dG. The high silibinin levels achieved in the human colorectal mucosa after consumption of safe silibinin doses support its further exploration as a potential human colorectal cancer chemopreventive agent.

Combined Treatment with Silibinin and Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors Overcomes Drug Resistance Caused by T790M Mutation

“…The peak plasma level of silibinin reached more than 100 mmol/L in phase I and pharmacodynamic studies, although it ranged from 10 to 100 mmol/L in recommended doses showing tolerable toxicity profiles (34,35). Because the present results were obtained mostly with 100 mmol/L of silibinin, further studies were done using a lower dose of silibinin to better define its clinical feasibility.…”

“…Although a higher dose of silibinin inhibited EGFR activation in cells harboring wild-type EGFR, it was not observed in most clinically feasible doses, which could be estimated from a previous phase I study (34,35). This differential effect between cells with mutant EGFR and wild-type EGFR might be related to the basal status of EGFR dimerization and cellular dependency for survival to EGFR signaling.…”

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

“…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).…”

Silibinin synergizes with mitoxantrone to inhibit cell growth and induce apoptosis in human prostate cancer cells

“…Since the half-life of oral silibinin in humans is short, 39 the in vitro efficacy of short duration treatments of silibinin was studied. First, the cells were treated with mitoxantrone for 2 hr, after which time the media was replaced with either standard media or media containing silibinin (20 lM).…”

“…38 This high-dose regimen is in contrast to a recent pharmacokinetic study of standard dose silibinin (1.4 g daily) in colorectal cancer patients, which demonstrated that measurable tissue levels were achievable at that dosing level, with a terminal plasma half-life of 3.4 hr. 39 Although, preclinical data would support the use of silibinin in combination with doxorubicin, cisplatin and carboplatin, these agents are not commonly used in the treatment of prostate cancer. Docetaxel, a microtubule inhibitor, is currently a first-line chemotherapy agent in advanced prostate cancer.…”