Suberoylanilide hydroxamic acid enhances chemosensitivity to 5-fluorouracil in hepatocellular carcinoma via inhibition of thymidylate synthase
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Hepatocellular carcinoma (HCC) is associated with a high rate of mortality worldwide. Here, we investigated the effect of combination treatment with suberoylanilide hydroxamic acid (SAHA) and 5-fluorouracil (5-FU) on HCC cells. HepG2, SMMC7721, and BEL7402 cells were treated with SAHA and/or 5-FU and subjected to cell viability, colony formation, and soft agarose assays; cell cycle, apoptosis, and reverse transcription-PCR analyses; western blotting; immunohistochemistry; and xenograft tumorigenicity assay. SAHA and 5-FU inhibited the proliferation of the three cell lines, and combination treatment with SAHA and 5-FU resulted in a combination index <1 and a dose-reduction index value >1, indicating a synergistic effect. Co-treatment with SAHA and 5-FU caused G0/G1 phase arrest and induced caspase-dependent apoptosis, inhibiting tumorigenicity in vitro and in vivo. 5-FU upregulated thymidylate synthase, whereas SAHA downregulated its expression. Our results indicate that SAHA and 5-FU act synergistically to inhibit cell growth and tumorigenicity in HCC via the induction of cell-cycle arrest and apoptosis through a mechanism involving the inhibition of thymidylate synthase, suggesting that combination treatment with 5-FU and SAHA may be beneficial for the treatment of inoperable HCC.
KeywordsHepatocellular carcinoma Suberoylanilide hydroxamic acid 5-fluorouracil Combination Thymidylate synthase
This work was supported by the State Key Project on Infectious Diseases of China (Grant Nos. 2012ZX10002016-004, 2012ZX10002010-001-004), the National Natural Science Foundation of China (Nos. 81372495 and 81372327) and Hubei Province for the Clinical Medicine Research Centre of Hepatic Surgery (2014BKB0892012DCA130032013BCB026). The authors thank Arian Laurence for his assistance in revising the manuscript.
Conflicts of interest
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