Combined treatment targeting HIF‐1α and Stat3 is a potent strategy for prostate cancer therapy

Abstract

The Stat3 pathway and the hypoxia-sensing pathway are both up-regulated in prostate cancer. Stat3 is a specific regulator of pro-carcinogenic inflammation and represents a promising therapeutic target. Hypoxia-inducible factor-1 (HIF-1)α, which mediates the cellular response to hypoxia, has been demonstrated to be over-expressed in many human cancers and is associated with poor prognosis and treatment failure in clinic. To develop a potent strategy to increase therapeutic efficacy and reduce drug resistance in prostate cancer therapy, we combined two anti-cancer agents: T40214 (a p-Stat3 inhibitor) and JG244 (a HIF-1α inhibitor) together to treat nude mice bearing human prostate tumor (DU145) and immunocompetent mice (C57BL/6) bearing murine prostate tumor (TRAMP-C2). We employed in vitro and in vivo assays, including Western blots, cell cycle analysis, immunohistochemistry, TUNEL and xenograft models to determine the drug efficacy and mechanism of combination treatment of T40214 and JG244. We found that compared to treatment by T40214 or JG244 alone, the combination treatment using T40214 and JG244 together significantly suppressed growth of human or murine prostate tumors. Also, compared with apoptotic cells induced by T40214 or JG244 alone, the combined treatment greatly increased apoptosis in DU145 (P < 0.006) and TRAMP-C2 tumors (P < 0.008). Our results suggested that combination treatment including a HIF-1α/2α inhibitor not only has therapeutic efficacy in targeting HIF-1α/2α, but also could reduce the hypoxia-induced drug resistance to other therapies (e.g., T40214) and enhance drug efficacy. This approach could make prostate cancer treatments more effective.