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The impact of NAD metabolism on cancer is particularly complex, because cells need adequate NAD to protect themselves against DNA damage and cancer, and the immune system needs NAD to fight cancer cells, but some cancers rely on NAD levels to reproduce.

ARTICLE: Does NR Cause Cancer?

 

Here are the studies:

Jan 23, 2023

Cancer - Breast

Oncogene

NAD+ supplementation limits triple-negative breast cancer metastasis via SIRT1-P66Shc signaling

Jiang, Yi

Summary

Here, we show that NAD+ supplement suppresses tumor metastasis in a Triple Negative Breast Cancer Model...Overall, we demonstrate that NAD+ supplementation executes its anti-tumor function via activating the SIRT1-p66Shc axis, which highlights the preventive and therapeutic potential of SIRT1 activators as effective interventions for TNBC.

Dec 27, 2022

Cancer - Chemotherapy

Cells

Nicotinamide Mononucleotide Administration Prevents Doxorubicin-Induced Cardiotoxicity and Loss in Physical Activity in Mice

Margier, Marielle

Summary

NMN significantly increased tissue levels of NAD+ and its metabolites and improved survival and bodyweight loss in both experimental models. In addition, NMN protected against Doxo-induced cardiotoxicity and loss of physical function in acute and chronic studies, respectively. In the heart, NMN prevented Doxo-induced transcriptomic changes related to mitochondrial function, apoptosis, oxidative stress, inflammation and p53, and promyelocytic leukemia nuclear body pathways. Overall, our results suggest that NMN could prevent Doxo-induced toxicity in heart and skeletal muscle.

Dec 2, 2022

Cancer - Chemotherapy

Preprint

The CD73 immune checkpoint promotes tumor cell metabolic fitness

Allard, David

Summary

We demonstrated that CD73 promote tumor growth in a cancer-cell autonomous manner by increasing metabolic fitness. This in turn favors cancer cell adaptation to nutrient-deprived microenvironments and cytotoxic stress by increasing OXPHOS, aspartate biosynthesis and DNA repair. Our study highlights new therapeutic opportunities that may be exploited in novel combination anti-cancer strategies.

Oct 28, 2022

Cancer - Chemotherapy

Reproduction

Intravenous Nicotinamide Riboside Administration Has a Cardioprotective Effect in Chronic Doxorubicin-Induced Cardiomyopathy

Podyacheva, Ekaterina

Summary

We demonstrated that NR intravenous administration decreases cardiac-muscle fibrous-tissue formation in chronic doxorubicin-induced cardiotoxicity development...Moreover, a pronounced protective effect of NR on the cardiovascular system was demonstrated...Simultaneously, the preventive NR administration had a more significant protective effect on the animal’s body as a whole.

Oct 1, 2022

Cancer - Breast

Biosensors and Bioelectronics

A bioluminescent-based probe for in vivo non-invasive monitoring of nicotinamide riboside uptake reveals a link between metastasis and NAD+ metabolism

Maric, Tamara

Summary

Our results demonstrate that NR supplementation results in a significant increase in cancer prevalence and metastases of TNBC to the brain. These results outline the important role of powerful nutraceuticals like NR in cancer metabolism and the need to personalize their use in certain patient populations.

Oct 1, 2022

Cancer - Skin

Journal of Drugs in Dermatology

A Narrative Review of Nicotinamide Adenine Dinucleotide (NAD)+ Intermediates Nicotinamide Riboside and Nicotinamide Mononucleotide for Keratinocyte Carcinoma Risk Reduction

Kahn, Benjamin

Summary

Oral nicotinamide (NAM) supplementation has been shown to decrease the incidence of keratinocyte carcinoma (KC) in high-risk skin cancer patients. NAM is a nicotinamide adenine dinucleotide (NAD+) intermediate and thus directly leads to increased NAD+. This increase in NAD+ is believed to be responsible for NAM’s impact on keratinocyte carcinoma risk. NAD+ has protective cellular effects and is a necessary cofactor for DNA repair, helping to prevent potentially oncogenic mutations. Nicotinamide riboside (NR) and nicotinamide mononucleotide (NMN) are NAD+ intermediates like NAM...

Jul 22, 2022

Brain - Cancer - NRH

Cancers (Basel)

Overcoming Temozolomide Resistance in Glioblastoma via Enhanced NAD+ Bioavailability and Inhibition of Poly-ADP-Ribose Glycohydrolase

Li, Jianfeng

Summary

Using the NAD precursor NRH to raise NAD levels in an incurable type of brain cancer (Glioblastoma multiforme or GBM) significantly increased the effectiveness of a type of chemotherapy (Temozolomide or TMZ) that is commonly used to treat GBM.

Jul 15, 2022

Metabolism - Cancer - Niacin

Pharmaceuticals

Structure-Based Identification and Biological Characterization of New NAPRT Inhibitors

Franco, Jorge

Summary

NAPRT displays marked tissue [specificity] and is mostly present in several catabolic healthy mammalian tissues including the heart, kidney, liver, and small intestine. In tissues that express the NAPRT protein, NA is the preferred precursor of NAD.

Jun 27, 2022

Neurons - Neuropathy - Cancer - Chemotherapy

Neuro-Oncology Advances

Nicotinamide riboside alleviates cisplatin-induced peripheral neuropathy via SIRT2 activation

Acklin, Scarlett

Summary

We show that NR, an NAD+ precursor and pharmacologic activator of SIRT2, effectively prevents and alleviates CIPN in mice. We present in vitro and in vivo genetic evidence to illustrate the specific dependence on SIRT2 of NR-mediated CIPN mitigation. Importantly, we demonstrate that NAD+ mediates SIRT2-dependent neuroprotection without inhibiting cisplatin cytotoxic activity against cancer cells. NAD+ may, in fact, further sensitize certain cancer cell types to cisplatin.

May 23, 2022

NAM - Cancer - Prostate

Frontiers in Molecular Biosciences

CD38-Induced Apoptosis and Mitochondrial Damage is Restored by Nicotinamide in Prostate Cancer

Kanayama, Mayuko

Summary

...CD38 expression is consistently silenced by methylation in prostate cancer and progressively downregulated in advanced castration-resistant prostate cancer, suggesting a connection between NAD+ and prostate carcinogenesis as well as prostate cancer progression. ...In this study, we...demonstrate that CD38 overexpression resulted in growth suppression and apoptosis accompanied by cleavage of poly (ADP-ribose) polymerase 1 (PARP1). CD38 overexpression also dramatically reduced intracellular NAD+ levels and decreased mitochondrial respiration as measured by oxygen consumption rate. We further show that some but not all of these CD38-induced phenotypes could be rescued by exogenous NAM. Treatment of cells with NAM rescued CD38-induced apoptosis and mitochondrial stress but did not restore intracellular NAD+ levels. We also found that NAM demonstrated biphasic effect on mitochondria function, a finding that can be explained by the dual role of NAM as both a precursor of NAD+ and also as a suppressor of a number of NAD+-dependent enzymes...

Apr 8, 2022

Cancer - Leukemia - Gut Microbiome

Cell Death & Disease

Gut microbiota severely hampers the efficacy of NAD-lowering therapy in leukemia

ElMokh, Oussama

Summary

Antibiotic therapy down-modulating gut microbiota can restore the anti-cancer efficacy of APO866. Alternatively, NAphosphoribosyltransferase inhibition may restore anti-cancer activity of NAMPT inhibitors in the presence of gut microbiota and of NAM in the diet.

Apr 7, 2022

Cancer - NF1

Cell Death & Differentiation

Tumor growth of neurofibromin-deficient cells is driven by decreased respiration and hampered by NAD+ and SIRT3

Masgras, Ionica

Summary

Upon neurofibromin loss, hyperactivation of Ras/MEK/ERK signaling inhibits complex I, causing a decrease in the NAD+/NADH ratio and the ensuing SIRT3 repression. Raising the NAD+/NADH ratio via NDI1 expression has an antineoplastic effect through the enhancement of SIRT3 activity...These findings indicate that tumorigenic growth of NF1-related neoplasms can be impaired both by TRAP1 ablation and by SIRT3 re-activation. Combination of these two approaches reaches maximal efficacy when SIRT3 induction is achieved through a rise in NAD+ precursors...These observations point toward a bona fide tumor suppressor role for SIRT3, which is abrogated by respiratory complex I inhibition and the ensuing decrease of NAD+/NADH ratio in NF1-related tumor cells...We envision that enhancement of SIRT3 activity and replenishment of NAD+ levels result in a multifaceted metabolic rewiring, which can oppose NF1-related cancer growth by affecting multiple bioenergetic pathways.

Mar 22, 2022

Gut Microbiota - Cancer

Frontiers in Molecular Biosciences

Interventions in Nicotinamide Adenine Dinucleotide Metabolism, the Intestinal Microbiota and Microcin Peptide Antimicrobials

Baquero, Fernando

Summary

New possibilities for employing NAD + boosting agents as modulators of the intestinal microbiota should be considered for fostering repopulation of microbiota after decontaminating antibiotic therapy...If certain pathogens increase in abundance, NAD boosting might favor beneficial organisms, particularly in combination with probiotics, prebiotics, or fecal transplantation...If the intestinal microbiota increases the effect of NAD boosting drugs, their concomitant use with antimicrobial agents should be prescribed only in patients where the presence of neoplastic disease can be ruled out.

Mar 12, 2022

Cancer - Breast

Molecular Oncology

Nicotinamide (niacin) supplement increases lipid metabolism and ROS-induced energy disruption in triple-negative breast cancer: potential for drug repositioning as an anti-tumor agent

Jung, Minsun

Summary

We showed strong evidence that NAM suppresses tumour growth and metastasis in TNBC. These findings indicate a promising potential of repositioning NAM supplement as a novel agent targeting cancer metabolism in TNBC...The activities of the key apoptosis-inducing processes upregulated by NAM are generally decreased in TNBC, supporting a potential therapeutic value of NAM in patients with TNBC.

Oct 5, 2020

Cancer

Nature Immunology

Disturbed mitochondrial dynamics in CD8+ TILs reinforce T cell exhaustion

Yu, Yi-Ru

Summary

The metabolic challenges present in tumors attenuate the metabolic fitness and antitumor activity of tumor-infiltrating T lymphocytes (TILs). However, it remains unclear whether persistent metabolic insufficiency can imprint permanent T cell dysfunction. We found that TILs accumulated depolarized mitochondria as a result of decreased mitophagy activity and displayed functional, transcriptomic and epigenetic characteristics of terminally exhausted T cells. Mechanistically, reduced mitochondrial fitness in TILs was induced by the coordination of T cell receptor stimulation, microenvironmental stressors and PD-1 signaling. Enforced accumulation of depolarized mitochondria with pharmacological inhibitors induced epigenetic reprogramming toward terminal exhaustion, indicating that mitochondrial deregulation caused T cell exhaustion. Furthermore, supplementation with nicotinamide riboside enhanced T cell mitochondrial fitness and improved responsiveness to anti-PD-1 treatment. Together, our results reveal insights into how mitochondrial dynamics and quality orchestrate T cell antitumor responses and commitment to the exhaustion program.

Oct 1, 2020

Neurons - Neuropathy - Cancer

Pain

Nicotinamide riboside relieves paclitaxel-induced peripheral neuropathy and enhances suppression of tumor growth in tumor-bearing rats

Hamity, Marta

Summary

Nicotinamide riboside (NR) is a vitamin B3 precursor of NAD that blunts diabetic and chemotherapy-induced peripheral neuropathy in preclinical models. This study examined whether NR also blunts the loss of intraepidermal nerve fibers induced by paclitaxel, which is associated with peripheral neuropathy...Unexpectedly, concomitant administration of NR during paclitaxel treatment further decreased tumor growth; thereafter, tumor growth resumed at the same rate as vehicle-treated controls. Administration of NR also decreased the percentage of Ki67-positive tumor cells in these rats...These results further support the ability of NR to play a protective role after nerve injury. They also suggest that NR may not only alleviate peripheral neuropathy in patients receiving taxane chemotherapy, but also offer an added benefit by possibly enhancing its tumor-suppressing effects.

Mar 3, 2020

Gut Microbiota - Cancer

Cell Metabolism

Bacteria boost mammalian host NAD metabolism by engaging the deamidated biosynthesis pathway

Shats, Igor

Summary

Nicotinamide adenine dinucleotide (NAD), a cofactor for hundreds of metabolic reactions in all cell types, plays an essential role in metabolism, DNA repair, and aging. However, how NAD metabolism is impacted by the environment remains unclear. Here, we report an unexpected trans-kingdom cooperation between bacteria and mammalian cells wherein bacteria contribute to host NAD biosynthesis. Bacteria confer resistance to inhibitors of NAMPT, the rate-limiting enzyme in the amidated NAD salvage pathway, in cancer cells and xenograft tumors. Mechanistically, a microbial nicotinamidase (PncA) that converts nicotinamide to nicotinic acid, a precursor in the alternative deamidated NAD salvage pathway, is necessary and sufficient for this protective effect. Using stable isotope tracing and microbiota-depleted mice, we demonstrate that this bacteria-mediated deamidation contributes substantially to the NAD-boosting effect of oral nicotinamide and nicotinamide riboside supplementation in several tissues. Collectively, our findings reveal an important role of bacteria-enabled deamidated pathway in host NAD metabolism.

Dec 24, 2019

CD38 - Cancer - Metabolism

Cells

The Good, the Bad and the Unknown of CD38 in the Metabolic Microenvironment and Immune Cell Functionality of Solid Tumors

Konen, Jessica

Summary

...The metabolic microenvironment within solid tumors has proven to be an important regulator of both the natural suppression of immune cell functionality and the de novo or acquired resistance to immunotherapy. Enzymatic proteins that generate immunosuppressive metabolites like adenosine are thus attractive targets to couple with immunotherapies to improve clinical efficacy. CD38 is one such enzyme. While the role of CD38 in hematological malignancies has been extensively studied, the impact of CD38 expression within solid tumors is largely unknown, though most current data indicate an immunosuppressive role for CD38. However, CD38 is far from a simple enzyme, and there are several remaining questions that require further study. To effectively treat solid tumors, we must learn as much about this multifaceted protein as possible....CD38 inhibition would likely have unforeseen effects, as it is a highly complex molecule capable of numerous functions

Aug 6, 2019

Cancer - Colon

Frontiers in Oncology

NAMPT and NAPRT, Key Enzymes in NAD Salvage Synthesis Pathway, Are of Negative Prognostic Value in Colorectal Cancer

Li, Xioa-quin

Summary

Nicotinamide adenine dinucleotide (NAD) is a profoundly important cofactor in redox reactions. Nicotinamide phosphoribosyltransferase (NAMPT) and nicotinate phosphoribosyltransferase (NAPRT) are key enzymes for NAD salvage biosynthesis pathway, which reciprocally synthesize NAD to supply the main source of NAD biosythesis. However, the prognostic value of NAMPT and NAPRT in colorectal cancer (CRC) remains largely unknown. Our present study detected NAMPT and NAPRT protein expression in cancer and adjacent tissues from 261 CRC using immunohistochemical staining. We found that high expression of NAMPT or NAPRT was associated with vascular invasion, invasion depth and advanced TNM stage in CRC. High expression of NAMPT or NAPRT predicts short overall survival and disease-free survival time in CRC patients, which were further confirmed by public datasets...

Oct 25, 2018

Cancer - Skin

Experimental Dermatology

Nicotinamide for photoprotection and skin cancer chemoprevention: A review of efficacy and safety

Snaidr, Victoria A.

Summary

The future of NAM as a photoprotective agent is promising, with this paper highlighting its positive safety profile and showing evidence supporting its utility in those patients at high risk for the development of non-melanoma skin cancer.

NAD Research - Cancer / Chemo

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