Chemoprevention of Lung Carcinogenesis by Dietary Nicotinamide and Inhaled Budesonide

Galbraith, Arthur R.; Seabloom, Donna E.; Wuertz, Beverly R.; Antonides, Jennifer D.; Steele, Vernon E.; Wattenberg, Lee W.; Ondrey, Frank G.

doi:10.1158/1940-6207.capr-17-0402

Cited by 10 publications

(9 citation statements)

References 50 publications

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“…The latter effect has been linked with reduced tumor infiltration by CD68 + inflammatory macrophages 40 , which is in line with our observations in the therapeutic setting. In a preclinical model of benzo(a)pyrene-induced lung carcinogenesis, oral (but not nasal) administration of NAM also demonstrated oncopreventive effects 41 . Thus, NAM might exert a relative broad oncosuppressive action, contrasting with other vitamins such as pyridoxine and calcitriol, which failed to enable oncoprevention in observational or interventional clinical studies 42 – 44 .…”

Section: Discussionmentioning

confidence: 99%

Immunoprophylactic and immunotherapeutic control of hormone receptor-positive breast cancer

et al. 2020

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Hormone receptor (HR)+ breast cancer (BC) causes most BC-related deaths, calling for improved therapeutic approaches. Despite expectations, immune checkpoint blockers (ICBs) are poorly active in patients with HR+ BC, in part reflecting the lack of preclinical models that recapitulate disease progression in immunocompetent hosts. We demonstrate that mammary tumors driven by medroxyprogesterone acetate (M) and 7,12-dimethylbenz[a]anthracene (D) recapitulate several key features of human luminal B HR+HER2− BC, including limited immune infiltration and poor sensitivity to ICBs. M/D-driven oncogenesis is accelerated by immune defects, demonstrating that M/D-driven tumors are under immunosurveillance. Safe nutritional measures including nicotinamide (NAM) supplementation efficiently delay M/D-driven oncogenesis by reactivating immunosurveillance. NAM also mediates immunotherapeutic effects against established M/D-driven and transplantable BC, largely reflecting increased type I interferon secretion by malignant cells and direct stimulation of immune effector cells. Our findings identify NAM as a potential strategy for the prevention and treatment of HR+ BC.

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Section: Discussionmentioning

confidence: 99%

Immunoprophylactic and immunotherapeutic control of hormone receptor-positive breast cancer

et al. 2020

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“…Dietary NAM suppressed lung tumor formation in benzo(a)pyrene-exposed animal models, either when administered alone or synergistically with budesonide [75] Animal models…”

Section: Skinmentioning

confidence: 99%

“…NAM suppressed the formation of bladder tumors in BBN (N-butyl-N-(4-hydroxybutyl)-nitrosamine)-exposed animal models [74]. It also suppressed lung tumor formation in benzo(a)pyrene-exposed animal models, either when administered alone or synergistically with the glucocorticoid budesonide [75], in addition to urethane-exposed animal models [76]. Likewise, NAM suppressed liver tumor development in thioacetamide-exposed [78] or the formation of pre-neoplastic lesions in DEN (diethylnitrosamine)-exposed animal models, showing it plays a role in the early stages of cancer development [77].…”

Section: Skinmentioning

confidence: 99%

The Role of Nicotinamide in Cancer Chemoprevention and Therapy

2020

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Nicotinamide (NAM) is a water-soluble form of Vitamin B3 (niacin) and a precursor of nicotinamide-adenine dinucleotide (NAD+) which regulates cellular energy metabolism. Except for its role in the production of adenosine triphosphate (ATP), NAD+ acts as a substrate for several enzymes including sirtuin 1 (SIRT1) and poly ADP-ribose polymerase 1 (PARP1). Notably, NAM is an inhibitor of both SIRT1 and PARP1. Accumulating evidence suggests that NAM plays a role in cancer prevention and therapy. Phase III clinical trials have confirmed its clinical efficacy for non-melanoma skin cancer chemoprevention or as an adjunct to radiotherapy against head and neck, laryngeal, and urinary bladder cancers. Evidence for other cancers has mostly been collected through preclinical research and, in its majority, is not yet evidence-based. NAM has potential as a safe, well-tolerated, and cost-effective agent to be used in cancer chemoprevention and therapy. However, more preclinical studies and clinical trials are needed to fully unravel its value.

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“…It is a NAD + precursor; its effects have been investigated in energy and Reactive Oxygen Species (ROS) production [ 30 ], as well as in inflammation control [ 31 , 32 ]. Given its central role in controlling energy production and the activity of many enzymes, NAM has been proposed in the treatment of several clinical conditions, including chemoprevention of non-melanoma skin cancer [ 12 , 21 , 33 ] and chemoprevention of lung cancer [ 34 ]. We have recently identified novel molecules showing anti-melanoma activity and characterized their mechanism of action [ 35 – 39 ].…”

Section: Introductionmentioning

confidence: 99%

Nicotinamide inhibits melanoma in vitro and in vivo

Scatozza

Moschella

D’Arcangelo

et al. 2020

J Exp Clin Cancer Res

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Background Even though new therapies are available against melanoma, novel approaches are needed to overcome resistance and high-toxicity issues. In the present study the anti-melanoma activity of Nicotinamide (NAM), the amide form of Niacin, was assessed in vitro and in vivo. Methods Human (A375, SK-MEL-28) and mouse (B16-F10) melanoma cell lines were used for in vitro investigations. Viability, cell-death, cell-cycle distribution, apoptosis, Nicotinamide Adenine Dinucleotide+ (NAD+), Adenosine Triphosphate (ATP), and Reactive Oxygen Species (ROS) levels were measured after NAM treatment. NAM anti-SIRT2 activity was tested in vitro; SIRT2 expression level was investigated by in silico transcriptomic analyses. Melanoma growth in vivo was measured in thirty-five C57BL/6 mice injected subcutaneously with B16-F10 melanoma cells and treated intraperitoneally with NAM. Interferon (IFN)-γ-secreting murine cells were counted with ELISPOT assay. Cytokine/chemokine plasmatic levels were measured by xMAP technology. Niacin receptors expression in human melanoma samples was also investigated by in silico transcriptomic analyses. Results NAM reduced up to 90% melanoma cell number and induced: i) accumulation in G1-phase (40% increase), ii) reduction in S- and G2-phase (about 50% decrease), iii) a 10-fold increase of cell-death and 2.5-fold increase of apoptosis in sub-G1 phase, iv) a significant increase of NAD+, ATP, and ROS levels, v) a strong inhibition of SIRT2 activity in vitro. NAM significantly delayed tumor growth in vivo (p ≤ 0.0005) and improved survival of melanoma-bearing mice (p ≤ 0.0001). About 3-fold increase (p ≤ 0.05) of Interferon-gamma (IFN-γ) producing cells was observed in NAM treated mice. The plasmatic expression levels of 6 cytokines (namely: Interleukin 5 (IL-5), Eotaxin, Interleukin 12 (p40) (IL12(p40)), Interleukin 3 (IL-3), Interleukin 10 (IL-10) and Regulated on Activation Normal T Expressed and Secreted (RANTES) were significantly changed in the blood of NAM treated mice, suggesting a key role of the immune response. The observed inhibitory effect of NAM on SIRT2 enzymatic activity confirmed previous evidence; we show here that SIRT2 expression is significantly increased in melanoma and inversely related to melanoma-patients survival. Finally, we show for the first time that the expression levels of Niacin receptors HCAR2 and HCAR3 is almost abolished in human melanoma samples. Conclusion NAM shows a relevant anti-melanoma activity in vitro and in vivo and is a suitable candidate for further clinical investigations.

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Chemoprevention of Lung Carcinogenesis by Dietary Nicotinamide and Inhaled Budesonide

Cited by 10 publications

References 50 publications

Immunoprophylactic and immunotherapeutic control of hormone receptor-positive breast cancer

Immunoprophylactic and immunotherapeutic control of hormone receptor-positive breast cancer

The Role of Nicotinamide in Cancer Chemoprevention and Therapy

Nicotinamide inhibits melanoma in vitro and in vivo

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