Abstract
Chemoresistance of colorectal cancer (CRC) leads to tumor recurrence and metastasis and new strategies are urgently needed to improve the outcomes of conventional chemotherapy. Sirtuin (SIRT) inhibitors prevent tumor cell growth by increasing the levels of acetylated histones and non-histones, as well as disrupting survival-related pathways. The aim of the present study was to determine the effect of SIRT inhibitors on CRC chemotherapy. The CompuSyn software program was used to evaluate the synergistic or antagonistic effects of various drugs, and the status of the protein deacetylation regulatory genes in microarray datasets were analyzed using bioinformatics. In HCT116 cells expressing wild-type (wt) TP53, SIRT inhibitors were found to act antagonistically with multiple chemotherapeutic agents (cisplatin, 5-fluorouracil, oxaliplatin, gefitinib, LY294002 and metformin), and decreased the anti-tumor effects of these agents. By contrast, SIRT inhibitors sensitized TP53-mutant (mut) SW620 cells to various chemotherapeutic drugs. Bioinformatics analysis indicated that SIRT1 and protein deacetylation related genes were highly expressed in TP53wt CRC cells when compared to TP53mut cells. Therefore, it was hypothesized that the likely mechanism underlying the antagonistic effect of SIRT inhibitors on TP53wt CRC cells was a reduction in the level of stable p53 protein. The present results indicated that divergent TP53 status may translate to a different chemosensitivity profile, and suggested that a combination therapy of SIRT inhibitors and first-line chemotherapeutic drugs may be beneficial for the treatment of patients with TP53mut CRC.