NAD- and NADPH-Contributing Enzymes as Therapeutic Targets in Cancer: An Overview

Abstract

Actively proliferating cancer cells require sufficient amount of NADH and NADPH for biogenesis and to protect cells from the detrimental effect of reactive oxygen species. As both normal and cancer cells share the same NAD biosynthetic and metabolic pathways, selectively lowering levels of NAD(H) and NADPH would be a promising strategy for cancer treatment. Targeting nicotinamide phosphoribosyltransferase (NAMPT), a rate limiting enzyme of the NAD salvage pathway, affects the NAD and NADPH pool. Similarly, lowering NADPH by mutant isocitrate dehydrogenase 1/2 (IDH1/2) which produces D-2-hydroxyglutarate (D-2HG), an oncometabolite that downregulates nicotinate phosphoribosyltransferase (NAPRT) via hypermethylation on the promoter region, results in epigenetic regulation. NADPH is used to generate D-2HG, and is also needed to protect dihydrofolate reductase, the target for methotrexate, from degradation. NAD and NADPH pools in various cancer types are regulated by several metabolic enzymes, including methylenetetrahydrofolate dehydrogenase, serine hydroxymethyltransferase, and aldehyde dehydrogenase. Thus, targeting NAD and NADPH synthesis under special circumstances is a novel approach to treat some cancers. This article provides the rationale for targeting the key enzymes that maintain the NAD/NADPH pool, and reviews preclinical studies of targeting these enzymes in cancers.

NAD+ metabolism, stemness, the immune response, and cancer

“…It has been shown that D-2HG suppress NAPRT expression by hypermethylation at CpG island of the NAPRT promoter. 219 , 225 , 226 Recently, it has been reported that the Protein Phosphatase Mg 2+ /Mn 2+ Dependent 1D (PPM1D) can also inhibit NAPRT expression. PPM1D is an oncogene involved in DNA damage response and cellular checkpoint pathways.…”

NADPH homeostasis in cancer: functions, mechanisms and therapeutic implications

“…Subsequently, the dehydrogenases/reductases in various metabolic pathways convert NADP + into NADPH. 10,12 NADKs are found in almost all human organs except skeletal muscle, and localized in both cytosol and mitochondria. Compared to cytosolic NADK (cNADK), mitochondrial NADK (mNADK) has a distinctive feature that it can directly phosphorylate nicotinamide adenine dinucleotide (NADH) to generate NADPH to alleviate oxidative stress in mitochondria.…”

“…First, NADPH is an essential cofactor of glutathione reductase (GR) and TRXR in GSH and TRX-peroxiredoxin (PRX) system, respectively, and reactivates catalase (CAT) to deactivate ROS for antioxidation; Second, NADPH is a crucial electron source for DHFR, Fe/S, POR, FANS, HMGCR, DPYD contributing to several reductive synthesis reactions, such as FAS, non-essential amino acids, nucleotides, and steroids synthesis; Third, NADPH is a substrate for NOXs to generate ROS The Cancer Genome Atlas (TCGA) database indicates both cNADK overexpression and the presence of several cNADK mutants in multiple tumor types. 10 Notably, a novel cNADK mutant, NADK-I90F, is found in pancreatic ductal adenocarcinoma cancer (PDAC) patients. CNADK-I90F has a lower K m and higher V max for NAD + compared to wild-type cNADK, which indicates increased enzyme activity.…”

“…The Cancer Genome Atlas (TCGA) database indicates both cNADK overexpression and the presence of several cNADK mutants in multiple tumor types. 10 Notably, a novel cNADK mutant, NADK-I90F, is found in pancreatic ductal adenocarcinoma cancer (PDAC) patients. CNADK-I90F has a lower K m and higher V max for NAD + compared to wild-type cNADK, which indicates increased enzyme activity.…”

“…A growing body of evidence has shown that regeneration and maintenance of the cellular NADP(H) content is strongly implicated in a variety of pathological conditions, such as diabetes, cardiovascular disease, neurodegenerative diseases, aging, 4 , 5 especially in tumorigenesis and cancer progression. 10 Compared with non-tumor cells, tumor cells usually maintain high levels of NADPH, not only to power redox defense but also to use for biosynthetic reactions to sustain their rapid growth. 5 , 11 This realization has prompted molecular studies of NADPH metabolism and its exploitation for the development of anticancer agents.…”