Enhancement of oxaliplatin-induced cell apoptosis and tumor suppression by 3-methyladenine in colon cancer.

Abstract

Oxaliplatin (OX) has been widely used in adjuvant and palliative treatments of advanced colon cancer; however, cancer cells ultimately become resistant in the majority of cases. Therefore, the development of a novel strategy to overcome this resistance is important for the effective treatment of colon cancer. Cell autophagy reduces the sensitivity of cancer cells to therapeutic reagents in various types of human cancer; therefore, the present study used murine CT26 colon carcinoma cells to explore whether inhibition of autophagy by 3-methyladenine (3-MA) is able to enhance OX-induced apoptosis in vitro and OX-suppressed tumor growth in vivo. CT26 cells were treated with 3-MA, OX, or 3-MA plus OX, and the autophagy, apoptosis and proliferation of the CT26 cells was investigated. Additionally, the therapeutic efficiency of the combination of 3-MA and OX treatment was evaluated in vivo by determining the survival time of the tumor-bearing mice and, thus, tumor growth rate. The treatment of CT26 cells in vitro with OX alone increased autophagy as well as apoptosis, whereas treatment with 3-MA plus OX markedly inhibited OX-induced autophagy, but increased OX-induced cell apoptosis. Furthermore, the combination of OX and 3-MA treatment significantly suppressed tumor growth in vivo and prolonged mouse survival time when compared with OX treatment alone. Similarly, 3-MA increased OX-induced cell apoptosis and decreased autophagy in xenograft tumor tissues. Thus, the administration of 3-MA may increase tumor cell sensitivity to OX by reducing its autophagic effects and enhancing its apoptotic effects. Data obtained in the present study indicates that the clinical combination of an autophagy inhibitor with OX may increase the therapeutic effect of OX and improve the clinical outcome of patients with colon cancer.