Abstract 674: Novel combinatorial quinacrine cancer therapies for advanced colon cancer

Abstract

Abstract BACKGROUND: Although treatments have improved patient prognosis in early stages of colorectal cancer, new effective drugs with improved safety profiles are needed for improving the treatment of patients with advanced colon cancer. Quinacrine, a small molecule anti-malarial agent that has activity in giardiasis, lupus, prion disease, and used as a means of non-surgical sterilization, has shown cytotoxic activity across a broad range of cancers. The well characterized safety profile of quinacrine and its anticancer activity hold promise in novel combinatorial cancer therapies. OBJECTIVES: To evaluate the potential of adding quinacrine to anticancer chemotherapeutics and targeted agents as a potential novel combinatorial therapy for advanced colon cancer and to detail the mechanism of action of quinacrine when combined with cancer chemotherapy and targeted agents. METHODS: In vitro dose-response curves and isobolograms were constructed for single agent and dual agent therapies using quinacrine, 5-fluorouracil, gemcitabine, and sorafenib using the following colon cancer cell lines: HT-29, HT-29-luc, HCT-15, HCT-116, HCT-116 p53−/−, HCT-116 bax−/−, RKO, DLD-1, SW-480, and SW-620. Western blot analysis and flow cytometry were used to investigate potential mechanisms of action and to examine cell death. In vivo experiments were carried out to investigate toxicity and efficacy of combinatorial quinacrine chemotherapy in an athymic nu/nu mouse tumor xenograft model with human HT-29-luc cells. RESULTS: Single-agent quinacrine demonstrates potent anticancer activity with an average IC50 of 5.79 ± 0.83 μM across all ten colon cancer cell lines screened. In combination, quinacrine enhanced the anticancer activity of 5-fluorouracil and gemcitabine while significantly synergizing with sorafenib. Western blot analysis revealed that quinacrine's anticancer activity partially arises from its ability to stabilize p53, elevate death receptor levels, and lower anti-apoptotic protein levels. Quinacrine, when combined with sorafenib, dramatically lowers levels of the anti-apoptotic protein MCL-1. In vivo studies have shown that quinacrine monotherapy at a daily dose of 150 mg/kg significantly lowers the tumor load of nu/nu mice. CONCLUSIONS: Quinacrine is cytotoxic to a broad range of colon cancer cells lines and enhances the anticancer activity of chemotherapies such as 5-fluorouracil, gemcitabine, and sorafenib. The administration of quinacrine in combination with chemotherapy agents and targeted agents in patients with advanced colon cancer should be further explored in the clinic. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 674. doi:10.1158/1538-7445.AM2011-674