5-FU resistance abrogates the amplified cytotoxic effects induced by inhibiting checkpoint kinase 1 in p53-mutated colon cancer cells
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 inhi...
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Veröffentlicht in: | International journal of oncology 2015-01, Vol.46 (1), p.63-70 |
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Sprache: | eng |
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Zusammenfassung: | 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 chemo-resistant 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 (ATM) 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/ATM 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. |
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ISSN: | 1019-6439 1791-2423 |
DOI: | 10.3892/ijo.2014.2693 |