Isosilibinin inhibits advanced human prostate cancer growth in athymic nude mice: comparison with silymarin and silibinin.
Earlier studies have shown the cancer chemopreventive efficacy of silymarin and its semi-purified constituent silibinin against prostate cancer (PCa), but the efficacy of other constituents of silymarin is largely unknown. In the present study, we assessed the in vivo growth inhibitory efficacy of one such constituent isosilibinin (a 50:50 mixture of isosilybin A and isosilybin B) in comparison with silymarin and silibinin in human PCa DU145 xenograft in athymic nude mice. Isosilibinin feeding (200 mg/kg body weight per day) significantly inhibited the growth of xenograft after 53 days of treatment (p < or = 0.005), which was equally or slightly better effective than silymarin and silibinin, respectively. Treatment with isosilibinin, silymarin and silibinin was stopped after 53 days and tumor volume was measured till 77 days. After 24 days of treatments withdrawal, tumor volume remain decreased, however, it was statistically significant only with isosilibinin (p < or = 0.05), suggesting its prolonged effect. Biomarker analysis showed that isosilibinin, silymarin and silibinin treatment for 53 days significantly inhibited the immunoreactivity for proliferating cell nuclear antigen (PCNA), microvessel density (CD31) and vascular endothelial growth factor along with significant increase in apoptotic cell population. The PCNA levels in tumors remained significantly low even after 24 days of treatments withdrawal. Western blot analysis of tumor tissue suggested that these flavonolignan formulations differentially alter the expression of cell cycle regulatory molecules, cyclins and Cdks. Overall, the results of present study suggest that isosilibinin has comparatively better efficacy against PCa and should be further analyzed for its clinical utility.
Deep
Gagan
G
Department of Pharmaceutical Sciences, School of Pharmacy, University of Colorado Denver, Denver, CO 80262, USA.
Raina
Komal
K
Singh
Rana P
RP
Oberlies
Nicholas H
NH
Kroll
David J
DJ
Agarwal
Rajesh
R
D020533:Angiogenesis Inhibitors / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D008833:Microcirculation / Q000187:drug effects; D018809:Proliferating Cell Nuclear Antigen / Q000276:immunology; D011471:Prostatic Neoplasms / Q000098:blood supply / Q000276:immunology / Q000517:prevention & control*; D000077385:Silybin; D012838:Silymarin / Q000031:analogs & derivatives* / Q000494:pharmacology*; D013997:Time Factors; D014183:Transplantation, Heterologous; D042461:Vascular Endothelial Growth Factor A / Q000187:drug effects
D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; D018809:Proliferating Cell Nuclear Antigen; D012838:Silymarin; D042461:Vascular Endothelial Growth Factor A; D000077385:Silybin; C075820:isosilybin