Nicotinamide N-Methyltransferase: An Emerging Protagonist in Cancer Macro(r)evolution

Parsons, Richard B.; Facey, Paul D.

doi:10.3390/biom11101418

Cited by 15 publications

(11 citation statements)

References 233 publications

(343 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…For many years, NNMT was merely considered an enzyme participating in phase II metabolism, able to N -methylate pyridine-like compounds, mainly modulating intracellular NAM levels. However, in the last decades, a great number of studies reporting NNMT upregulation in association with cancer have been published, thus evidencing an increasing interest in the speculating function exerted by the enzyme in the context of malignant transformation [ 110 ]. Results of these works overall demonstrate that the significance of NNMT upregulation in cancer is strictly related to its ability to promote a wide range of cellular pathways and processes featuring tumor initiation and progression, such as cell proliferation, migration, invasion, and resistance to chemotherapy.…”

Section: Discussionmentioning

confidence: 99%

Nicotinamide N-Methyltransferase as Promising Tool for Management of Gastrointestinal Neoplasms

2022

View full text Add to dashboard Cite

Gastrointestinal (GI) neoplasms include esophageal, gastric, colorectal, hepatic, and pancreatic cancers. They are characterized by asymptomatic behavior, being responsible for diagnostic delay. Substantial refractoriness to chemo- and radiotherapy, exhibited by late-stage tumors, contribute to determine poor patient outcome. Therefore, it is of outmost importance to identify new molecular targets for the development of effective therapeutic strategies. In this study, we focused on the enzyme nicotinamide N-methyltransferase (NNMT), which catalyzes the N-methylation reaction of nicotinamide and whose overexpression has been reported in numerous neoplasms, including GI cancers. The aim of this review was to report data illustrating NNMT involvement in these tumors, highlighting its contribution to tumor cell phenotype. Cited works clearly demonstrate the interesting potential use of enzyme level determination for both diagnostic and prognostic purposes. NNMT was also found to positively affect cell viability, proliferation, migration, and invasiveness, contributing to sustain in vitro and in vivo tumor growth and metastatic spread. Moreover, enzyme upregulation featuring tumor cells was significantly associated with enhancement of resistance to treatment with chemotherapeutic drugs. Taken together, these results strongly suggest the possibility to target NNMT for setup of molecular-based strategies to effectively treat GI cancers.

show abstract

Section: Discussionmentioning

confidence: 99%

Nicotinamide N-Methyltransferase as Promising Tool for Management of Gastrointestinal Neoplasms

2022

View full text Add to dashboard Cite

show abstract

“…The analyzed clinical trials were built on this concept. However, special consideration should be given to the fact that some enzymes determining NAD+ levels have been related to cancer progression, at least at an experimental level ( 38 ).…”

Section: Discussionmentioning

confidence: 99%

NAD+-Increasing Strategies to Improve Cardiometabolic Health?

et al. 2022

View full text Add to dashboard Cite

Depleted nicotinamide adenine dinucleotide (NAD+) is a common hallmark of metabolic disorders. Therefore, NAD+-increasing strategies have evolved as a potential therapeutic venue to combat cardiometabolic diseases. Several forms of vitamin B3, i.e., nicotinamide and nicotinamide mononucleotide, and especially nicotinamide riboside, have attracted most interest as potentially safe and efficacious candidates for NAD+ restoration. Herein, we dissected the characteristics of the latest clinical trials testing the therapeutic potential of different vitamin B3 molecules to improve cardiometabolic health, with a special focus on randomized, placebo-controlled clinical trials performed in the context of obesity or other pathologies, mainly linked to cardiovascular system and skeletal muscle functionality. The favorable outcomes via NAD+-increasing strategies found in the different studies were quite heterogeneous. NAD+-increasing interventions improved capacity to exercise, decreased blood pressure, increased the anti-inflammatory profile and insulin-stimulated glucose disposal, and reduced the fat-free mass. Except for the decreased blood pressure, the significant results did not include many hard clinical end points, such as decreases in weight, BMI, fasting glucose, or HbA1c percentage. However, the analyzed trials were short-term interventions. Overall, the accumulated clinical data can be interpreted as moderately promising. Additional and long-term studies will be needed to directly compare the doses and duration of treatments among different vitamin B3 regimes, as well as to define the type of patients, if any, that could benefit from these treatments. In this context, a major point of advancement in delineating future clinical trials would be to identify subjects with a recognized NAD+ deficiency using novel, appropriate biomarkers. Also, confirmation of gender-specific effect of NAD+-increasing treatments would be needed.

show abstract

“…8 NNMT overexpression is observed in cancer, including high-grade serous carcinoma (HGSC) 9 and other conditions with poor prognosis. 10,11 NNMT was found to be upregulated in cancer-associated fibroblasts (CAFs) in patients with metastatic HGSC, and high NNMT levels were required to maintain the CAF phenotype. CAFs are components of the tumor microenvironment that can support tumor survival, growth, and metastasis.…”

Section: ■ Introductionmentioning

confidence: 99%

“…Single methoxy substitutions at the four-(9, nicotinamide numbering) or two- (10) positions lead to inactivity. Installation of a methylamine at the four-position produces a compound (11) with limited activity. Unsurprisingly, 4-methylnicotinamide ( 12) is an NNMT substrate.…”

Section: ■ Introductionmentioning

confidence: 99%

Potent Uncompetitive Inhibitors of Nicotinamide N-Methyltransferase (NNMT) as In Vivo Chemical Probes

et al. 2022

View full text Add to dashboard Cite

NNMT uses SAM as a cofactor to catalyze the methylation of nicotinamide, producing 1-methylnicotinamide. Recent studies have shown that NNMT upregulation in cancerassociated fibroblasts (CAFs) is required to maintain the CAF phenotype in high-grade serous carcinoma. These observations suggest that NNMT should be evaluated as a therapeutic target, especially in cancer. Although several small-molecule inhibitors of NNMT have been identified, there remains a need for highly potent and selective inhibitors with excellent in vivo activity and ADME properties that can be used as reliable chemical probes. We have identified azaindoline carboxamide 38 as a selective and potent NNMT inhibitor with favorable PK/PD and safety profiles as well as excellent oral bioavailability and pharmaceutical properties. Our mechanistic studies indicate that 38 binds uncompetitively with SAM but competitively with nicotinamide consistent with its binding in the nicotinamide binding site and likely forming a positive interaction with SAM.

show abstract

Nicotinamide N-Methyltransferase: An Emerging Protagonist in Cancer Macro(r)evolution

Cited by 15 publications

References 233 publications

Nicotinamide N-Methyltransferase as Promising Tool for Management of Gastrointestinal Neoplasms

Nicotinamide N-Methyltransferase as Promising Tool for Management of Gastrointestinal Neoplasms

NAD+-Increasing Strategies to Improve Cardiometabolic Health?

Potent Uncompetitive Inhibitors of Nicotinamide N-Methyltransferase (NNMT) as In Vivo Chemical Probes

Contact Info

Product

Resources

About