Background: Dichloroacetate (DCA) and metformin (M) have been reported to have many effects on cancer cells including alterations in pH homeostasis and glucose metabolism, cell cycle arrest, induction of autophagy and modulation of the tumor microenvironment. These effects have been shown to increase tumor apoptosis, inhibit neoplastic cell proliferation, improve the immune response against tumor cells and decrease the protective inflammatory response in tumors, which has led to the investigation of these drugs as anticancer agents. This study examines the effects of DCA and metformin in a murine colon cancer model both in vivo and in vitro.
Methods: Murine colon cancer cell lines (ATCC CT26-CL25, CT26-WT) and cells isolated from subcutaneous metastatic colon cancer tumors (CT71911) were grown in the presence of DCA (serial concentrations from 12 mM to 192mM) and M (serial concentrations from 8 mM to 48 mM). Viable cells were counted and averaged for 3 separate assays. Balb/c mice in triplicate were injected IP with serial concentrations of DCA and M (8,24,48 mM) beginning one day prior to tail vein administration of 7.5 x 103 colon cancer cells (CT26-WT, CT71911). Daily IP injections of DCA and M were continued for 6 weeks or until the mice succumbed to metastatic cancer. All mice were autopsied and cause of death was recorded.
Results: All three cell lines demonstrated a linear reduction in growth and increased apoptosis with increasing concentrations of DCA. All tumor cells were killed at concentrations above 96 mM. M was cytostatic but not cytotoxic for all three cell lines with minimal growth at 8 mM and no growth at higher concentrations. In vivo, administration of IP DCA prolonged survival by 80 - 89% (days after tumor challenge), while IP metformin prolonged survival by 35 - 38%. Increased survival with both DCA and M was not dose dependent with variation between concentrations less than 10%. All mice died of lung metastases.
Conclusion: Both DCA and M demonstrated beneficial effects on murine colon cancer cells with reductions in cell growth and increased apoptosis in vitro and increased survival in vivo. M exhibited cytostatic activity and a lower improvement in survival while DCA exhibited cytotoxic activity and a longer survival benefit. Further investigation in the use of these agents as adjunct therapies for colon cancer is warranted.
Citation Format: Robert P. Sticca, Tonya C. Murphy. Effects of DCA and metformin on murine colon cancer growth. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3793. doi:10.1158/1538-7445.AM2014-3793