title: Silibinin synergizes with mitoxantrone to inhibit cell growth and induce apoptosis in human prostate cancer cells.
abstract: The purpose of these experiments was to assess the synergistic activity of silibinin with chemotherapy agents in clinical use against prostate cancer. Silybin-phytosome, a commercially available formulation containing silibinin, has recently been studied in a phase I clinical trial. The silibinin doses used in the present study are clinically achievable based on the preliminary phase I data. DU145, PC-3 and LNCaP prostate cancer cells were seeded in 96-well plates in triplicate. Twenty-four hours later, silibinin (10, 20 and 40 microM) and either mitoxantrone or docetaxel were added to the designated wells. Seventy-two hours post-treatment, cell viability was determined with a tetrazolium-based assay. The combination index (CI) for determination of a synergistic effect was calculated, with values of <0.9 indicating synergy and values >1.1 antagonism. Apoptosis was also assessed using a luminescent assay after 72 hr of treatment with media alone, silibinin, mitoxantrone, or silibinin plus mitoxantrone. Silibinin showed a synergistic effect with mitoxantrone, as measured by reduction in cell viability. The CI values ranged from 0.413 to 2.650 for the combination of silibinin and mitoxantrone; in contrast, treatment with docetaxel and silibinin showed little or no synergy, with CI values of 0.898-4.469. In concordance with these findings, the addition of silibinin increased the level of apoptosis compared to mitoxantrone alone, particularly in the PC-3 cells. The combination of silibinin and mitoxantrone exhibits a pattern of synergy in reducing cell viability with increased apoptosis. These data are important in the planning of future clinical applications of silibinin.
authors.affiliation: Department of Medicine, University of Colorado at Denver and Health Sciences Center, Aurora, CO, USA. thomas.flaig@uchsc.edu
authors.forename: Thomas W
authors.initials: TW
authors.lastname: Flaig
authors.forename: Lih-Jen
authors.initials: LJ
authors.lastname: Su
authors.forename: Gail
authors.initials: G
authors.lastname: Harrison
authors.forename: Rajesh
authors.initials: R
authors.lastname: Agarwal
authors.forename: Leonard Michael
authors.initials: LM
authors.lastname: Glodé
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004249:DNA Damage; D004357:Drug Synergism; D006801:Humans; D008297:Male; D008942:Mitoxantrone / Q000494:pharmacology*; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000473:pathology; D000077385:Silybin; D012838:Silymarin / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; D012838:Silymarin; D000077385:Silybin; D008942:Mitoxantrone