Abstract
Abstract Binding of TRAIL to death receptors (TRAIL-R1/DR4 and TRAIL-R2/DR5) induces apoptosis in cancer cells without affecting normal cells. The purpose of this study was to identify and characterize TRAIL-death receptor agonist (DRA) that induces apoptosis in breast cancer cells. DRA is a small organic molecule. The pharmacokinetics of the DRA with a single oral dose was also characterized in nude mice. Blood was collected over 72-hour period after DRA administration, and analyzed by HPLC-MS/MS for plasma drug concentration. The Cmax, tmax, and AUC of DRA were measured. DRA inhibited cell viability and colony formation, and induced apoptosis in estrogen-dependent (MCF-7) and independent (MDA-MB-231 and MDA-MB-468) human breast cancer cell lines, but had no effect on human normal mammary epithelial cells and hepatocytes. The combination of DRA with paclitaxel or doxorubicin had synergistic effects on apoptosis in breast cancer cell lines. DRA formed active TRAIL-DISC (death-inducing signaling complex) similar to that of TRAIL. DRA inhibited the growth of orthotopically implanted MDA-MB-231 and MDA-MB-468 tumors in nude mice. Histological examination of tumor tissues derived from DRA-treated nude mice revealed massive caspase-3 activation and apoptosis. Pharmacokinetic data demonstrate that DRA possesses a long terminal half-life, which is acceptable for further clinical development. In conclusion, we have identified DRA that can be used either alone or in combination with chemotherapeutic drugs for the treatment of human breast cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 258. doi:1538-7445.AM2012-258
Published Version
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