期刊
EXPERIMENTAL AND THERAPEUTIC MEDICINE
卷 20, 期 2, 页码 1415-1422出版社
SPANDIDOS PUBL LTD
DOI: 10.3892/etm.2020.8818
关键词
sirtuin inhibitors; chemotherapy; TP53; colorectal cancer
资金
- National Natural Science Foundation of China [81903065, 81803581]
- Shanghai Key Laboratory of Molecular Imaging [18DZ2260400]
- Collaborative Innovation Key Project of Shanghai University of Medical and Health Sciences [SPCI-18-18-003]
- Program for Professor of Special Appointment at Shanghai Institutions of Higher Learning [TP2018080]
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 sensitizedTP53-mutant (mut) SW620 cells to various chemotherapeutic drugs. Bioinformatics analysis indicated that SIRT1 and protein deacetylation related genes were highly expressed inTP53(wt)CRC cells when compared toTP53(mut)cells. Therefore, it was hypothesized that the likely mechanism underlying the antagonistic effect of SIRT inhibitors onTP53(wt)CRC cells was a reduction in the level of stable p53 protein. The present results indicated that divergentTP53status 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 withTP53(mut)CRC.
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