Novel antivascular efficacy of metronomic docetaxel therapy in prostate cancer: hnRNP K as a player

Abstract

Tumor growth requires a competent vascular supply and angiogenesis is now considered a potential target for cancer treatment. Chemotherapeutic drugs, and docetaxel in particular, chronically administered using a frequent schedule at low dose (metronomic dosing), can cause potent antiangiogenic effects by targeting the endothelial cells of newly growing blood vessels. Because the exposure to cytotoxic drugs could target both endothelial and tumor cells, we investigated the effects of "metronomic docetaxel" on hormone refractory prostate carcinoma cells. In vitro, metronomic therapy lowered tumor cell viability, inducing apoptosis and reducing the invasive potential at 10- to100-fold lower concentrations as compared with the maximum tolerated dose. Metronomic regimens resulted in a significant reduction of vascular endothelial cell growth factor expression and up-regulation of endogenous angiogenesis inhibitors. Our studies suggest that heterogeneous nuclear ribonucleoprotein K is a mediator of the effects we observed. Targeting heterogeneous nuclear ribonucleoprotein K may serve as a specific antimetastasis and antiangiogenic therapy and could be a potential predictive marker to determine the optimal dose and schedule for metronomic chemotherapy regimens. These findings highlight the multiple effects that may characterize antiangiogenic metronomic chemotherapy and suggest that docetaxel might act as antitumor compound by affecting both cancer and endothelial cells at the same drug concentration. Careful optimization of drug scheduling and dosages will be required to maximize antitumor responses with metronomic approaches.