Development of a Combination Therapy for Prostate Cancer by Targeting Stat3 and HIF-1alpha
Abstract
The Stat3 pathway and the hypoxia sensing pathway are both upregulated in prostate cancer. Stat3 is a specific regulator of pro-carcinogenic inflammation and represents a promising therapeutic target for converting cancer-promoting inflammation to anti-tumor immunity. HIF-1 which mediates the cellular response to hypoxia, has been demonstrated to be overexpressed 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-1 inhibitor) together to treat nude mice bearing human prostate tumor (DU145), and immunocompetent mice (C57BL/6) bearing murine prostate tumor (TRAMP-C2). The results showed that targeting p-Stat3 and HIF-1 together greatly promoted drug efficacy as compared to either agent used alone. Western blots and TUNEL assays provided evidence that, compared with each agent alone, the combination treatment dramatically increased apoptosis in tumors and enhanced drug efficacy, suggesting that the combination treatment including a HIF-1 /2 inhibitor not only has therapeutic efficacy in targeting HIF-1 /2 but can also reduce hypoxia-induced drug resistance and enhance drug efficacy for the combined therapeutic agents, potentially making standard prostate cancer treatments more effective.
Document Details
- Document Type
- Technical Report
- Publication Date
- Jul 01, 2011
- Accession Number
- ADA548791
Entities
People
- Naijie Jing
Organizations
- Baylor College of Medicine