The mediating role of caspase-3 protease in the intracellular mechanism of genistein-induced apoptosis in human prostatic carcinoma cell lines, DU145 and LNCaP.
A series of in vitro studies were carried out to investigate genistein-induced cell death, and the nature of cell death, in two human prostate cancer cell lines (LNCaP and Du145), and the possible involvement of caspase-3 protease in genistein-induced apoptosis in the target cells. The major findings of these studies are: i) genistein inhibits growth and proliferation of both LNCaP and DU145 cells via apoptosis mainly, and necrosis at higher concentrations; ii) genistein induces activation and expression of caspase-3 (CPP32) in both target cells; iii) genistein-induced apoptosis and CPP32 activation could be significantly inhibited by the caspase-3 inhibitor, z-VAD-fmk (N-benzyloxycarbonyl-Val-Asp-fluoromethyl-ketone), thus confirming a mediator role of CPP32 in the genistein-induced apoptotic pathway in the target cells. The potency of most known chemopreventive drugs for cancer is due to induction of apoptosis in solid tumors (Thompson, Science 267 (1995) 1456; Gurney et al., Science 288 (2000) 283). Inevitably, agents that increase transcription of caspase-3 protease could reinforce cell death via CPP32-mediated apoptosis. In this regard, genistein may find an application in the treatment of human prostate carcinoma, independently of hormone sensitivity.
Kumi-Diaka
J
J
Department of Biology, College of Liberal Arts and Sciences, Florida Atlantic University, Davie 33314, USA. jdiaka@acc.fau.edu
Sanderson
N A
NA
Hall
A
A
D000590:Amino Acid Chloromethyl Ketones / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D006690:Bisbenzimidazole / Q000493:pharmacokinetics; D002277:Carcinoma / Q000188:drug therapy* / Q000201:enzymology / Q000503:physiopathology; D053148:Caspase 3; D020169:Caspases / Q000187:drug effects* / Q000378:metabolism; D002455:Cell Division / Q000187:drug effects / Q000502:physiology; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D053938:DNA Fragmentation / Q000187:drug effects / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions / Q000502:physiology; D005456:Fluorescent Dyes / Q000493:pharmacokinetics; D019833:Genistein / Q000494:pharmacology*; D012739:Gonadal Steroid Hormones / Q000378:metabolism / Q000494:pharmacology; D006801:Humans; D020287:In Situ Nick-End Labeling; D008297:Male; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000503:physiopathology; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D014407:Tumor Cells, Cultured / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology
D000590:Amino Acid Chloromethyl Ketones; D000970:Antineoplastic Agents; D015853:Cysteine Proteinase Inhibitors; D005456:Fluorescent Dyes; D012739:Gonadal Steroid Hormones; C096713:benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone; D019833:Genistein; C505407:CASP3 protein, human; D053148:Caspase 3; D020169:Caspases; D006690:Bisbenzimidazole