Silibinin suppresses in vivo growth of human prostate carcinoma PC-3 tumor xenograft.
Chemoprevention is an upcoming approach to control cancer including prostate cancer (PCa). Here, we studied the efficacy and associated mechanisms of a chemopreventive agent silibinin against ectopically growing and established advanced human prostate carcinoma PC-3 tumor xenografts in athymic nude mice. Dietary silibinin (0.5%, w/w) did not show any adverse health effect in mice. In first protocol, silibinin started 1 week prior to xenograft implantation and continued for 60 additional days, whereas in the second protocol, silibinin treatment was started after 25 days of established tumors for 4, 8 and 16 days. Silibinin inhibited tumor growth rate in both protocols showing up to 35% (P = 0.010) and 18-56% (P = 0.002 to <0.001) decrease in tumor volume per mouse and 27% (P < 0.01) and 44% (P = 0.014) decrease in tumor weight per mouse, respectively. In first protocol, silibinin decreased (P < 0.001) tumor cell proliferation and microvessel density but increased (P < 0.001) apoptosis. An increase in insulin-like growth factor-binding protein-3 (IGFBP-3) expression with a concomitant decrease in vascular endothelial growth factor (VEGF) expression was noted. Silibinin strongly increased phospho-extracellular signal-regulated kinase 1/2 (ERK1/2), Cip1/p21 and Kip1/p27 (cyclin-dependent kinase inhibitors) levels but moderately decreased Bcl-2 and survivin levels. In established tumors, similar biomarkers and molecular changes were observed due to silibinin corresponding to its antitumor efficacy. These findings identified in vivo antitumor efficacy of silibinin against PC-3 human PCa in both intervention protocols accompanied with its anti-proliferative, pro-apoptotic and anti-angiogenic activities. At molecular level, silibinin increased IGFBP-3, Cip1/p21, Kip1/p27 levels and ERK1/2 activation and decreased Bcl-2, survivin and VEGF levels in tumors.
Singh
Rana P
RP
Department of Pharmaceutical Sciences, School of Pharmacy, University of Colorado at Denver and Health Sciences Center, Denver, CO 80262, USA.
Deep
Gagan
G
Blouin
Marie-José
MJ
Pollak
Michael N
MN
Agarwal
Rajesh
R
D000818:Animals; D016588:Anticarcinogenic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects*; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000378:metabolism; D004032:Diet; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins; D018972:Insulin-Like Growth Factor Binding Protein 3 / Q000378:metabolism; D008297:Male; D051379:Mice; D008819:Mice, Nude; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D009363:Neoplasm Proteins / Q000378:metabolism; D009368:Neoplasm Transplantation; D011471:Prostatic Neoplasms / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D000077385:Silybin; D012838:Silymarin / Q000008:administration & dosage / Q000494:pharmacology; D000077022:Survivin; D014183:Transplantation, Heterologous; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
D016588:Anticarcinogenic Agents; C107489:BIRC5 protein, human; C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D051034:Inhibitor of Apoptosis Proteins; D018972:Insulin-Like Growth Factor Binding Protein 3; D008869:Microtubule-Associated Proteins; D009363:Neoplasm Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D012838:Silymarin; D000077022:Survivin; D042461:Vascular Endothelial Growth Factor A; D050760:Cyclin-Dependent Kinase Inhibitor p27; D000077385:Silybin; D048049:Extracellular Signal-Regulated MAP Kinases