Department of Biochemistry, Faculty of Pharmaceutical Sciences, Tokyo University of Science, Noda, Chiba 278-8510, Japan; Department of Gene Regulation, Faculty of Pharmaceutical Sciences, Tokyo University of Science, Noda, Chiba 278-8510, Japan.
Department of Biochemistry, Faculty of Pharmaceutical Sciences, Tokyo University of Science, Noda, Chiba 278-8510, Japan.
Genomics. 2019 Dec;111(6):1889-1895. doi: 10.1016/j.ygeno.2018.12.012. Epub 2018 Dec 21.
Cancer cells' resistance to drugs remains an important problem affecting cancer treatment strategies. We previously studied the nicotinamide phosphoribosyltransferase (NAMPT) inhibitor FK866's resistance mechanisms in the human colorectal cancer HCT116 cells. We established an acquired FK866-resistant cell line, HCT116R. In this study, we investigated gene mutations in parental HCT116 and HCT116R cells using exome sequencing technology. The results indicated cluster genes related to NAD biosynthesis (including NAMPT), DNA repair, and ATP-binding cassette transporters were differentially altered in these cells. Interestingly, HCT116R cells, which are resistant to other class NAMPT inhibitors, were more sensitive to the anticancer 5-fluorouracil and cisplatin and γ-ray irradiation compared to parental HCT116 cells. This higher sensitivity appears to cause a genetic change in the identified gene clusters by resistance to the NAMPT inhibitor FK866. Collectively, these novel findings provide a better understanding of anticancer candidate NAMPT inhibitors with regard to resistance mechanisms and cancer chemotherapy strategies.
癌细胞对药物的耐药性仍然是影响癌症治疗策略的一个重要问题。我们之前研究了烟酰胺磷酸核糖转移酶（NAMPT）抑制剂 FK866 在人结直肠癌细胞 HCT116 中的耐药机制。我们建立了一个获得性 FK866 耐药细胞系 HCT116R。在这项研究中，我们使用外显子组测序技术研究了亲本 HCT116 和 HCT116R 细胞中的基因突变。结果表明，与 NAD 生物合成（包括 NAMPT）、DNA 修复和 ATP 结合盒转运体相关的簇基因在这些细胞中发生了差异改变。有趣的是，与亲本 HCT116 细胞相比，对其他类 NAMPT 抑制剂耐药的 HCT116R 细胞对抗癌药物 5-氟尿嘧啶、顺铂和γ射线照射更为敏感。这种更高的敏感性似乎是由对 NAMPT 抑制剂 FK866 的耐药性引起的对鉴定基因簇的遗传改变所致。总之，这些新发现为理解抗癌候选 NAMPT 抑制剂的耐药机制和癌症化疗策略提供了更好的认识。
