Synergistic antimicrotubule therapy for prostate cancer

Abstract

Prostate cancer has been widely viewed as a chemoresistant neoplasm. Perhaps, the most prevalent antimicrotubule strategy involves docetaxel administration at its maximum-tolerated dose (MTD). Although the goal is to obtain total eradication of cancer cells, debilitating toxicities are presented by docetaxel therapy, including myelosuppression, immunosuppression, gastrointestinal toxicity and peripheral neuropathy. In addition, solubility limitations necessitate infusion of high-doses intravenously once or twice a week followed by a rest period, which allows recovery of normal proliferating cells to counter-balance efficacy. An emerging notion is that more of a toxic drug at its MTD is not necessarily better. It is likely that combinatorial antimicrotubule therapy with drugs occupying different sites on tubulin may enhance efficacy while reducing toxicity. Here we show that bromonoscapine (EM011), a microtubule-modulating noscapine analog, displays synergism with docetaxel as seen by cell viability and proliferation assays. Cell-cycle data demonstrated that lower dose-levels of docetaxel (25nM) in combination with EM011 caused an additive increase in proapoptotic activity. Since docetaxel alone caused severe mitotic arrest followed by mitotic slippage and endoreduplication, we strategized a sequential treatment regime that involved initial pretreatment with docetaxel followed by addition of EM011 to maximize mitotic arrest and subsequent apoptosis. In vivo studies with docetaxel and EM011 in combination showed a marked inhibition of tumor growth compared to docetaxel or EM011 as single-agents. Our studies suggest the potential usefulness of EM011 in the clinic to enhance docetaxel activity. This would reduce toxicity, thus improving the quality of life of docetaxel-treated patients.