Triacanthine enhances the sensitivity of colorectal cancer cells to 5-fluorouracil by regulating RRM2

Background: According to the literatures, triacanthine is isolated from the leaves of Gleditsia triacanthos L. and acts as an anti -hypertensive agent, also cardiotonic, antispasmodic and a respiratory analeptic. The 5-fluorouracil (5 -FU) is widely used to treat the patients of colorectal cancer (CRC), but the resistance to 5 -FU treatment restricts the therapeutic efficacy of CRC patients. Purpose: This study aims to explore a novel therapeutics regimen overcoming CRC resistance to 5 -FU. Methods: The cell proliferation of CRC cells was determined by SRB and colony formation assay. Transwell and wound -healing assay were applied to explore the potential metastatic abilities of CRC cells. qRT-PCR and Western blot were performed to evaluate the level of indicated mRNAs and proteins respectively. Xenograft assay was used to explore the anti -CRC effect of triacanthine. Results: Triacanthine statistically restrained CRC proliferation both in vitro and in vivo. Triacanthine induced cell cycle G1/G0 phase arrest in CRC cells. Meanwhile, triacanthine also inhibited the migrative and invasive abilities of CRC cells. A Venn diagram was generated showing that O-6-Methylguanine-DNA Methyltransferase (MGMT) might be a molecular target of triacanthine in treating CRC. Furthermore, triacanthine plus 5 -FU significantly suppressed the cell proliferation of CRC cells compared with single agent treatment alone, and highly synergistic anti -cancer effects were scored when 5 -FU was combined with triacanthine in CRC cells. In addition, triacanthine sensitized the anti -cancer activity of 5 -FU via regulating Ribonucleotide Reductase Regulatory Subunit M2 (RRM2). MGMT or RRM2 might be novel biomarkers for evaluating the therapeutical efficiency of 5 -FU in CRC patients. Conclusion: We firstly demonstrated triacanthine suppressed cell proliferation and metastasis abilities and found the novel molecular targets of triacanthine in CRC cells. This is the first study to evaluate the anti -cancer efficiency of triacanthine plus 5 -FU. Our study has revealed triacanthine as a pertinent sensitizer to 5 -FU, and provided novel strategies for predicting outcomes and reversing resistance of 5 -FU therapy.