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Research ArticleExperimental Studies

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

YOKO OGINO, AKIRA SATO, YOHEI KAWANO, TAKAO AOYAMA, FUMIAKI UCHIUMI and SEI-ICHI TANUMA
Anticancer Research December 2019, 39 (12) 6457-6462; DOI: https://doi.org/10.21873/anticanres.13859
YOKO OGINO
1Department of Biochemistry, Faculty of Pharmaceutical Sciences, Tokyo University of Science, Noda, Japan
2Department of Gene Regulation, Faculty of Pharmaceutical Sciences, Tokyo University of Science, Noda, Japan
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AKIRA SATO
1Department of Biochemistry, Faculty of Pharmaceutical Sciences, Tokyo University of Science, Noda, Japan
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  • For correspondence: akirasat@rs.tus.ac.jp
YOHEI KAWANO
3Department of Pharmacotherapeutics, Faculty of Pharmaceutical Sciences, Tokyo University of Science, Noda, Japan
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TAKAO AOYAMA
3Department of Pharmacotherapeutics, Faculty of Pharmaceutical Sciences, Tokyo University of Science, Noda, Japan
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FUMIAKI UCHIUMI
2Department of Gene Regulation, Faculty of Pharmaceutical Sciences, Tokyo University of Science, Noda, Japan
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SEI-ICHI TANUMA
4Department of Genomic Medicinal Science, Research Institute for Science and Technology, Organization for Research Advancement, Tokyo University of Science, Noda, Japan
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Abstract

Background/Aim: 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. Materials and Methods: We used CRC human cell line HCT116 to determine the expression profiles of FK866-sensitive parental HCT116 cells and FK866-resistant HCT116 (HCT116RFK866) 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 HCT116RFK866 cells by co-treatment with MDR1 inhibitor verapamil. Results: Our results revealed an association between ATP-binding cassette (ABC) transporter gene ABCB1 and resistance to NAMPT inhibitor FK866 in both HCT116RFK866 cells and parental HCT116 cells. The expression of ABCB1, which encodes MDR1, was lower in HCT116RFK866 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 HCT116RFK866 cells than in parental HCT116 cells. Additionally, HCT116RFK866 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. Conclusion: 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.

  • ABC transporter
  • drug resistance
  • FK866
  • NAMPT
  • NAMPT inhibitor
  • verapamil
  • Received November 1, 2019.
  • Revision received November 11, 2019.
  • Accepted November 12, 2019.
  • Copyright© 2019, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved
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Anticancer Research: 39 (12)
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December 2019
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Association of ABC Transporter With Resistance to FK866, a NAMPT Inhibitor, in Human Colorectal Cancer Cells
YOKO OGINO, AKIRA SATO, YOHEI KAWANO, TAKAO AOYAMA, FUMIAKI UCHIUMI, SEI-ICHI TANUMA
Anticancer Research Dec 2019, 39 (12) 6457-6462; DOI: 10.21873/anticanres.13859

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Association of ABC Transporter With Resistance to FK866, a NAMPT Inhibitor, in Human Colorectal Cancer Cells
YOKO OGINO, AKIRA SATO, YOHEI KAWANO, TAKAO AOYAMA, FUMIAKI UCHIUMI, SEI-ICHI TANUMA
Anticancer Research Dec 2019, 39 (12) 6457-6462; DOI: 10.21873/anticanres.13859
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Keywords

  • ABC transporter
  • drug resistance
  • FK866
  • NAMPT
  • NAMPT inhibitor
  • verapamil
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