Chemosensitivity of human prostate cancer cells PC3 and LNCaP to genistein isoflavone and β-lapachone

Abstract

A wide spectrum of anti-cancer activity of genistein and β-lapachone in various tumors has been reported in single treatments. In this study the combined effects of genistein and β-lapachone on the chemosensitivity of LNCaP and PC3 human prostate cancer cells was determined in vitro, using 3-〚4,5-dimethylthiazol-2-yl〛-2-,5-diphenyltetrazolium bromide (MTT) and lactate dehydrogenase (LDH) to study treatment-induced growth inhibition and cytotoxicity and, annexin V–fluoresceine (FI) and terminal deoxyribonucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL)–propidium iodide (PI) assays to determine potential treatment-induced apoptosis and/or necrosis. The results showed: i) that both PC3 and LNCaP are sensitive to single and combination treatments regardless of hormone sensitivity status, ii) that treatment induced dual death pathways (apoptosis and necrosis) in both cell types, iii) that growth inhibition in both cell types correlated positively with cell death via apoptosis at lower drug concentrations and necrosis at higher concentrations, iv) that combination of genistein and β-lapachone had synergistic inhibitory effects on growth and proliferation in both cell types. The synergistic inhibitory effect was correlated positively with treatment-induced cell death via apoptosis and necrosis. The overall results indicate that combination treatments with β-lapachone and genistein are more potent in killing both PC3 and LNCaP cancer cells than treatment with either genistein or β-lapachone alone. β-lapachone acts at the G1 and S phase checkpoints in the cell cycle, while genistein induces cell cycle arrest at the G 2–M stage. The current results are therefore in agreement with the hypothesis that drug combinations that target cell cycles at different critical checkpoints would be more effective in causing cell death. This result provides a rationale for in vivo studies to determine whether β-lapachone–genistein combination will provide effective chemotherapy for prostate cancer, regardless of the tumor sensitivity to hormone.