The NAMPT Inhibitor FK866 in Combination with Cisplatin Reduces Cholangiocarcinoma Cells Growth

Kishor Pant; Seth Richard; Estanislao Peixoto; Jun Yin; Davis M Seelig; Pietro Carotenuto; Massimiliano Salati; Brunella Franco; Lewis R Roberts; Sergio A Gradilone

doi:10.3390/cells12050775

The NAMPT Inhibitor FK866 in Combination with Cisplatin Reduces Cholangiocarcinoma Cells Growth

Cells. 2023 Feb 28;12(5):775. doi: 10.3390/cells12050775.

Authors

Kishor Pant^{1

2}, Seth Richard¹, Estanislao Peixoto^{1

2}, Jun Yin³, Davis M Seelig⁴, Pietro Carotenuto^{5

6}, Massimiliano Salati^{7

8}, Brunella Franco^{6

9}, Lewis R Roberts¹⁰, Sergio A Gradilone^{1

2}

Affiliations

¹ The Hormel Institute, University of Minnesota, Austin, MN 55912, USA.
² Masonic Cancer Center, University of Minnesota, Minneapolis, MN 55455, USA.
³ Division of Clinical Trials and Biostatistics, Mayo Clinic, Rochester, MN 55905, USA.
⁴ Comparative Pathology Shared Resource, Masonic Cancer Center, College of Veterinary Medicine, University of Minnesota, St. Paul, MN 55108, USA.
⁵ Telethon Institute of Genetics and Medicine (TIGEM), 80078 Pozzuoli, Italy.
⁶ Medical Genetics, Department of Translational Medical Sciences, University of Naples Federico II, 80131 Naples, Italy.
⁷ Medical Oncology Unit, University Hospital of Modena, 41125 Modena, Italy.
⁸ Clinical and Experimental Medicine, University of Modena and Reggio Emilia, 411250 Modena, Italy.
⁹ Genomics and Experimental Medicine Program, Scuola Superiore Meridionale, School for Advanced Studies, 80131 Naples, Italy.
¹⁰ Department of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN 55905, USA.

Abstract

It is well established that Cholangiocarcioma (CCA) drug resistance plays a crucial role in the spread and survival of cancer cells. The major enzyme in the nicotinamide-adenine dinucleotide (NAD+)-mediated pathways, nicotinamide phosphoribosyltransferase (NAMPT), is essential for cancer cell survival and metastasis. Previous research has shown that the targeted NAMPT inhibitor FK866 reduces cancer cell viability and triggers cancer cell death; however, whether FK866 affects CCA cell survival has not been addressed before. We show herein that NAMPT is expressed in CCA cells, and FK866 suppresses the capacity of CCA cells to grow in a dose-dependent manner. Furthermore, by preventing NAMPT activity, FK866 significantly reduced the amount of NAD+ and adenosine 5'-triphosphate (ATP) in HuCCT1, KMCH, and EGI cells. The present study's findings further show that FK866 causes changes in mitochondrial metabolism in CCA cells. Additionally, FK866 enhances the anticancer effects of cisplatin in vitro. Taken together, the results of the current study suggest that the NAMPT/NAD+ pathway may be a possible therapeutic target for CCA, and FK866 may be a useful medication targeting CCA in combination with cisplatin.

Keywords: Cholangiocarcinoma; FK866; NAD; NAMPT; cisplatin.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adenosine Triphosphate / metabolism
Cell Proliferation
Cholangiocarcinoma*
Cisplatin* / pharmacology
Humans
NAD / metabolism
Nicotinamide Phosphoribosyltransferase / metabolism

Substances

Cisplatin
Nicotinamide Phosphoribosyltransferase
NAD
Adenosine Triphosphate

Grants and funding

This work was supported by The Hormel Foundation. Part of the study was kindly supported by POR CAMPANIA FESR 2014/2020 grant (Project titles: “Dalla genomica alla terapia di tumori rari” and “Combattere la resistenza tumorale: piattaforma integrata multidisciplinare per un approccio tecnologico innovativo alle concoterapie; CUP B61G18000470007) by the Italian Association for Cancer Research (AIRC) (grant n. IG 17711/2015 to B.F.). P.C. is a current recipient of a Marie Skłodowska-Curie Career Re-Integration fellowship funded by AIRC and the European Union’s Horizon 2020 research and innovation program (Grant agreement No 800924).