Silibinin synergizes with mitoxantrone to inhibit cell growth and induce apoptosis in human prostate cancer cells.
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.
Flaig
Thomas W
TW
Department of Medicine, University of Colorado at Denver and Health Sciences Center, Aurora, CO, USA. thomas.flaig@uchsc.edu
Su
Lih-Jen
LJ
Harrison
Gail
G
Agarwal
Rajesh
R
Glodé
Leonard Michael
LM
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
D000970:Antineoplastic Agents; D012838:Silymarin; D000077385:Silybin; D008942:Mitoxantrone