5-FU resistance abrogates the amplified cytotoxic effects induced by inhibiting checkpoint kinase 1 in p53-mutated colon cancer cells

Abstract

The emergence of chemoresistance is a major limitation of current cancer therapies, and checkpoint kinase (Chk1) 1 positively correlates with resistance to chemo-.or radio-therapy. Cancer cells lacking p53 pathways are completely dependent on the S and G2/M checkpoints via Chk1; therefore, Chk1 inhibition enhances the cytotoxicity of DNA-damaging agents only in p53-deficient cells. However, little is known about the synergistic effect of Chk1 inhibition with 5-FU, the most frequently used antimetabolite, in chemoresistant colorectal cells. In this study, we found that 5-FU induced S-phase arrest only in p53-deficient colorectal cancer cells. 5-FU treatment induced DNA damage and activation of ataxia telangiectasia mutated (AT M) and Chk1, leading to S-phase arrest, and Chk1 inhibition using SB218078 reduced S-phase arrest and increased apoptosis in the presence of 5-FU. In contrast, in p53-deficient, 5-FU-resistant (5FUR) colon cancer cells that we developed, 5-FU enhanced DNA damage but did not induce Chk1/AT M activation or cell cycle arrest. SB218078 in combination with 5-FU did not induce apoptosis. These results indicate that 5-FU- resistance abrogated the anticancer effect amplified by Chk1 inhibition, even in p53-deficient cancer cells.