Association of ABC Transporter With Resistance to FK866, a NAMPT Inhibitor, in Human Colorectal Cancer Cells

• Published in: Anticancer research 2019-12, Vol.39 (12), p.6457-6462
• Main Authors: Ogino, Yoko, Sato, Akira, Kawano, Yohei, Aoyama, Takao, Uchiumi, Fumiaki, Tanuma, Sei-Ichi
• Format: Article
• Language: English
• Subjects: ABC transporter; Acrylamides - pharmacology; ATP; ATP Binding Cassette Transporter, Subfamily B - genetics; ATP Binding Cassette Transporter, Subfamily B - metabolism; Binding; Cancer; Colorectal cancer; Colorectal carcinoma; Colorectal Neoplasms - genetics; Colorectal Neoplasms - metabolism; Cytokines - antagonists & inhibitors; Deoxyribonucleic acid; DNA; DNA chips; DNA microarrays; Down-Regulation; Drug resistance; Drug Resistance, Neoplasm; Drug Synergism; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; HCT116 Cells; Humans; Inhibitors; MDR1 protein; Multidrug resistance; Mutation; NAD; Nicotinamide; Nicotinamide phosphoribosyltransferase; Nicotinamide Phosphoribosyltransferase - antagonists & inhibitors; Oligonucleotide Array Sequence Analysis - methods; P-Glycoprotein; Phosphoribosyltransferase; Piperidines - pharmacology; Proteins; Sensitivity analysis; Verapamil; Verapamil - pharmacology
• ISSN: 0250-7005; 1791-7530
• DOI: 10.21873/anticanres.13859

Nicotinamide phosphoribosyltransferase (NAMPT), a key enzyme in the NAD biosynthetic pathway, is a drug target of potent anticancer candidates, including FK866 and other reported NAMPT inhibitors. However, it is known that NAMPT point-mutations render resistance to specific NAMPT inhibitors in several cancer cells. We investigated the resistance mechanisms of NAMPT inhibitor FK866 in human colorectal cancer (CRC) cells. We used CRC human cell line HCT116 to determine the expression profiles of FK866-sensitive parental HCT116 cells and FK866-resistant HCT116 (HCT116R ) cells by DNA microarray analysis. The levels of multidrug resistance protein 1 (MDR1) were assessed via western blot. In addition, we analyzed the sensitivity of FK866 in parental HCT116 cells and HCT116R cells by co-treatment with MDR1 inhibitor verapamil. Our results revealed an association between ATP-binding cassette (ABC) transporter gene ABCB1 and resistance to NAMPT inhibitor FK866 in both HCT116R cells and parental HCT116 cells. The expression of ABCB1, which encodes MDR1, was lower in HCT116R cells than in parental HCT116 cells. Furthermore, the protein level of MDR1/ATP-binding cassette sub-family B member 1 (ABCB1) was 0.5-fold lower in HCT116R cells than in parental HCT116 cells. Additionally, HCT116R cells showed improved sensitivity to FK866 when co-treated with verapamil, an ABCB1 inhibitor. Interestingly, the efficacy of FK866 in parental HCT116 cells was the same for the treatment with FK866 alone or in combination with verapamil. The change in expression of ABCB1 plays a key role in CRC drug resistance to NAMPT inhibitor FK866. This suggests that the MDR1/ABCB1 mechanism may regulate the resistance of anticancer NAMPT inhibitor FK866.