Mechanistic Study Of Inhibitory Effect Of Drug Combination On Prostate Cancer

Prostate cancer (PCa) is the second most common cancer in men. PCa accounts highest for the newly diagnosed cancers in recent years, especially in elder men. The death rate is higher than other cancers. Consequently, it is urgent to gain a better understanding on the mechanisms driving PCa in developed countries and to develop new agents. There are many factors that can cause prostate cancer, including aging, inheritance, hormone level and energy balance. Currently, the treatment of prostate cancer includes surgery and radiation therapy. Combination drug therapies for prostate cancer provide a new direction. The combination of different drugs may be an effective therapy for inhibiting the growth of prostate cancer with less side effect and lower toxicity.This study focused on the mechanisms by which cholesterol affects the growth and sensitivity of prostate cancer cells to docetaxel, and the mechanisms for growth inhibition and apoptosis induction by docetaxel alone or in combination with cholesterol-lowering drug atorvastatin. Prostate cancer PC-3 and LNCaP cells were used to investigate the effects and mechanisms of cholesterol and the drug combination. Cell growth and apoptosis were determined by the trypan blue exclusion assay and morphological assessment of cells stained with propidium iodide. NF-κB activity was determined by luciferase reporter gene assay and the Western blot assay was used to determine the levels of Bcl-2, phospho-Akt, VEGF, and phospho-Erkl/2. Results showed that lower concentrations of docetaxel in combination with atorvastatin produced a stronger inhibitory effect than docetaxel at higher concentrations in vitro and vivo. In the present study, we found that pre-treatment with cholesterol decreased the inhibitory effects of docetaxel on prostate cancer PC-3 cells, and demonstrated for the first time that the cholesterol-lowing drug atorvastatin combined with docetaxel at lower concentrations had even more potent effects on growth inhibition and apoptosis induction than either agent alone at higher concentrations. Mechanistic studies indicated that induction of apoptosis in PC-3 cells was associated with significant decreases in the levels of Bcl-2, VEGF, phospho-Akt, and phospho-Erkl/2. In animal experiment, SCID mice with PC-3 xenograft tumors were treated with docetaxel alone or in combination with atorvastatin. Combination of docetaxel and atorvastatin had stronger inhibitory effect on the growth of PC-3 tumors than either agent alone.The present study demonstrated for the first time that cholesterol decreased the sensitivity of prostate cancer cells to chemotherpeutic drugs. Cholesterol-lowering drugs such as atorvastatin increased the response of prostate cancer cells to docetaxel and thus decreased the concentration of this drug. Low dose docetaxel in combination with cholesterol lowering drug may increase the effectiveness of chemotherapy, reduce toxic side effect and drug resistance, and may represent a novel strategy for effective treatment of prostate cancer. Drug combination may be effective approach for inhibiting the growth of prostate cancer.