In cancer, all roads lead to NADPH

Gulam Mohmad Rather; Alvinsyah Adhityo Pramono; Zoltan Szekely; Joseph R Bertino; Philip Michael Tedeschi

doi:10.1016/j.pharmthera.2021.107864

In cancer, all roads lead to NADPH

Pharmacol Ther. 2021 Oct:226:107864. doi: 10.1016/j.pharmthera.2021.107864. Epub 2021 Apr 22.

Authors

Gulam Mohmad Rather¹, Alvinsyah Adhityo Pramono², Zoltan Szekely³, Joseph R Bertino⁴, Philip Michael Tedeschi¹

Affiliations

¹ Rutgers Cancer Institute of New Jersey, Rutgers, The State University of New Jersey, New Brunswick, NJ, USA.
² Rutgers Cancer Institute of New Jersey, Rutgers, The State University of New Jersey, New Brunswick, NJ, USA; Research Center of Medical Genetics, Faculty of Medicine, Universitas Padjadjaran, Bandung, Indonesia.
³ Rutgers Cancer Institute of New Jersey, Rutgers, The State University of New Jersey, New Brunswick, NJ, USA; Department of Pharmaceutics, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, NJ, USA; Department of Chemistry and Chemical Biology, Rutgers, The State University of New Jersey, Piscataway, NJ, USA.
⁴ Rutgers Cancer Institute of New Jersey, Rutgers, The State University of New Jersey, New Brunswick, NJ, USA; Department of Medicine and Pharmacology, Robert Wood Johnson Medical School, Rutgers, The State University of New Jersey, New Brunswick, NJ, USA. Electronic address: bertinoj@cinj.rutgers.edu.

PMID: 33894275
DOI: 10.1016/j.pharmthera.2021.107864

Abstract

Cancer cells require increased levels of NADPH for increased nucleotide synthesis and for protection from ROS. Recent studies show that increased NADPH is generated in several ways. Activated AKT phosphorylates NAD kinase (NADK), increasing its activity. NADP formed, is rapidly converted to NADPH by glucose 6-phosphate dehydrogenase and malic enzymes, overexpressed in tumor cells with mutant p53. Calmodulin, overexpressed in some cancers, also increases NADK activity. Also, in IDH1/2 mutant cancer, NADPH serves as the cofactor to generate D-2 hydroxyglutarate, an oncometabolite. The requirement of cancer cells for elevated levels of NADPH provides an opportunity to target its synthesis for cancer treatment.

Keywords: Calmodulin; NAD; NAD kinase; NADPH; ROS.

Publication types

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

MeSH terms

Humans
NADP* / metabolism
Neoplasms* / drug therapy
Neoplasms* / metabolism

Substances

NADP