XPF-ERCC1 blocker improves the therapeutic efficacy of 5-FU- and oxaliplatin-based chemoradiotherapy in rectal cancer

Abstract 5-FU-based chemoradiotherapy (CRT) and oxaliplatin-based CRT are commonly used therapies for advanced rectal cancer (RC). However, patients with high expression of ERCC1 have worse prognosis than those with low expression. In this study, we investigated the effect of XPF-ERCC1 blockers on chemotherapy and 5-FU-based CRT and oxaliplatin (OXA)-based CRT in rectal cancer cell lines. We investigated half maximal inhibitory concentration (IC50) of 5-FU, OXA, XPF-ERCC1 blocker, and XPF-ERCC1 blocker and 5-FU or OXA combined, and analyzed the effect of XPF-ERCC1 blocker on 5-FU-based CRT and oxaliplatin-based CRT. Furthermore, the expression of XPF and γ-H2AX in rectal cells was analyzed. In animal models, we combined XPF-ERCC1 blocker with 5-FU and OXA to investigate the effects of RC, and finally combined XPF-ERCC1 blocker with 5-FU- and oxaliplatin-based CRT. In the IC50 analysis of each compound, the cytotoxicity of the XPF-ERCC1 blocker was lower than that of 5-FU and OXA. In addition, XPF-ERCC1 blocker combined with 5-FU or OXA enhanced the cytotoxicity of the chemotherapy drugs in rectal cells. Furthermore, the XPF-ERCC1 blocker also increased the cytotoxicity of 5-FU-based CRT and OXA -based CRT by inhibiting the XPD product DNA locus. In vivo, the XPF-ERCC1 blocker was confirmed to enhance 5-FU, OXA, 5-FU-based CRT, and OXA CRT. These findings show that XPF-ERCC1 blockers cannot only increase the toxicity of chemotherapy drugs, but also increase the efficacy of combined chemoradiotherapy. In the future, the XPF-ERCC1 blocker may be used to improve the efficacy of 5-FU- and oxaliplatin-based CRT.