VITAMIN B3

Vitamin B3 nicotinamide – the niacinamide form has shown anti-cancer effects in clinical trials for non-melanoma skin cancers. Given the explosion in pre-cancerous actinic keratosis, basal cell and squamous cell carcinoma , there is a need for active supplements that can help slow and reduce lesions, many of which can be on the face.The main action of niacinamide is to increase immune cell metabolism and function, including reducing inflammatory responses. A promising supporting therapy with some evidence particularly in skin cancers.

Also a new trial in EFGR mutated lung cancers shows positive effects for women in the never smoking group. Clinical trials have been run around 1000mg (500mg x 2 daily). In a supplement plan for skin cancers and beyond there is likely a place for the nicotinamide / niacinamide form of B3, perhaps even the topical form which shows UV protective effects in research. Another developing area is so called Accelerated Radiotherapy with Carbogen and Nicotinamide (ARCON) mainly in head and neck cancer. New research in Non Hodgkins and Multiple Myelomas seem to exploit this in developing advanced adjuvant threrapy to oncology drugs ( see References). The niacin version of B3 has shown remarkably promising activity in pre-clinical trials for glioblastoma, and has ongoing phase I/II dose finding trials. (see Pathfinder)

There is population study evidence tying low levels of vitamin B3 to decreased risk in breast cancers. Whilst, conversely, higher levels of B1 were associated with increased risk. Whilst common in many foods, a supplement can needed to sustain the levels needed, evidence moderate in terms of preventative actions overall though some evidence has been shown (see Examples).

TYPICAL ABSORPTION LEVELS

High

EXAMPLES OF IMPROVED OUTCOMES

YES
ANALYSIS

PRE-DIAGNOSIS OR PREVENTION

MIXED
ANALYSIS

Highlighted Studies

At 12 months, the rate of new nonmelanoma skin cancers was lower by 23%..in the nicotinamide group than in the placebo group. Similar differences were found between the nicotinamide group and the placebo group with respect to new basal-cell carcinomas (20%) ..and new squamous-cell carcinomas (30%)..The number of actinic keratoses was 11% lower in the nicotinamide group

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During the 4-month trials, 11 placebo patients developed 20 new skin cancers (12 basal cell carcinoma (BCC) and 8 SCC) and 2 nicotinamide patients developed 4 cancers (2 BCC and 2 SCC). The odds of developing at least one skin cancer was significantly lower with nicotinamide (odds ratio=0.14).. as was the rate of new skin cancers (relative rate=0.24).. as estimated, respectively…adjusting for study and number of previous skin cancers

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Several studies, however, demonstrated that ACORN [ radiotherapy + niacinamide B3] may, at lower doses, improve outcomes among patients with other cancer types. A phase 3 study of 333 patients with locally advanced bladder cancer randomly assigned patients to receive ACORN (60 mg/kg nicotinamide) or radiotherapy alone.10 ACORN resulted in a prolonged Overall Survival (59% vs 46%) and improved recurrence-free survival (54% vs 43%) compared with placebo at 3 years.

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The levels of VitB1 and VitB5 in the serum of breast cancer patients and patients with benign breast diseases were higher than those in the healthy control group, while the expression levels of VitB3 in breast cancer patients were lower than those in the healthy control group and the breast benign disease groups. The level of VitB1 was positively correlated with breast cancer risk. The VitB3 level was negatively correlated with breast cancer risk. The VitB5 level is not significantly related ...

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TABLE OF REFERENCES

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https://bmccancer.biomedcentral.com/articles/10.1186/s12885-022-10265-45Meta-analysisA total of 3504 participants were included in the cohort, with 1054 deaths. One thousand eight hundred forty-seven participants (52.3%) were female, 2548 participants (73.4%) were white, and the mean age (SE) was 65.38 years (0.32). According to multivariate logistic regression analysis, niacin intake was negatively associated with mortality outcomes in patients with cancer, with P values below 0.05 in all models. In subgroup analyses based on sex, age, and BMI, the association persisted. The Kaplan-Meier curves indicate that high niacin intake groups have better survival rates than low intake groups. Niacin supplementation improved cancer mortality but not all-cause mortality.Our study found that higher intake of dietary niacin was associated with lower risk of mortality from all-causes and cancer mortality. The consumption of niacin had a dose-effect relationship for all-cause mortality, but not for cancer mortality. This conclusion was verified by the data of supplemental niacin consumption. The results of our study are consistent with those of other recent cohort studies. According to Chen F et al [22], dietary nutrition is associated with a lower mortality rate, while supplement intake can be harmful in excess. A meta-analysis of 13 trials revealed a tendency towards a lower risk of cardiovascular mortality
https://www.sciencedirect.com/science/article/pii/S26663791240043974.5To further explore the impact of VB3 supplementation on the prognosis of cancer patients, Kaplan-Meier analysis was employed to illustrate the correlation between VB3 supplementation and cancer-related death outcomes in the NHANES database. We found cancer patients who took VB3 supplementation had a lower cancer-related death rate (p < 0.001) (Figure 1C). Similarly, a lower cancer-related death risk was observed in digestive system cancer patients with VB3 supplementation, although the association was not statistically significant due to the limited population size of digestive system cancer patients in this analysisMechanically, the TME induces aberrant GPR109A/nuclear factor κB (NF-κB) activation in myeloid cell to shape the immunosuppressive TME. In contrast, VB3 activates β-Arrestin-mediated GPR109A degradation and NF-κB inhibition to suppress the immunosuppressive polarization of myeloid cell, thereby activating the cytotoxic function of CD8+ T cell. Overall, these results expand the understanding of how vitamins regulate the TME, suggesting that dietary VB3 supplementation is an adjunctive treatment for liver cancer.
https://www.nejm.org/doi/full/10.1056/NEJMoa15061974.5Human studyIn conclusion, among high-risk patients, nicotinamide was associated with a lower rate of new nonmelanoma skin cancers than was placebo and had an acceptable safety profile. Nicotinamide is widely accessible as an inexpensive over-the-counter vitamin supplement and presents a new opportunity for the chemoprevention of nonmelanoma skin cancers that is readily translatable into clinical practice.We found that nicotinamide had a good safety profile. Nicotinamide has been used at pharmacologic doses (up to 3 g daily) over many years with minimal side effects35 and is used clinically to treat autoimmune blistering disorders such as bullous pemphigoid, usually at doses of 1.5 g daily.36 Unlike nicotinic acid (niacin), nicotinamide does not cause vasodilatory side effects such as flushing, itching, hypotension, and headaches1000mg
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9125143/4Meta-analysis Nicotinamide was associated with a significant reduction in skin cancers compared to control (rate ratio 0.50 ) in 552 patients; across 5 trials; moderate strength of the evidence. Heterogeneity was explained by risk of bias. Nicotinamide was associated with a significant reduction in BCCs and cSCCs.No significant difference in means of AK was observed when nicotinamide was compared to control .... Subgroup analyses for AK are presented in the Supplemental material. Some concerns were brought regarding risk of bias in the randomization process in one trial, where baseline differences in number of AK favor participants randomized to nicotinamide (mean, 36.3) compared to control (mean, 30.0). 37 The strength of the evidence for AK was judged very low because of inconsistency
https://www.jidonline.org/article/S0022-202X(15)35732-8/fulltext4Human studyDuring the 4-month trials, 11 placebo patients developed 20 new skin cancers (12 basal cell carcinoma (BCC) and 8 SCC) and 2 nicotinamide patients developed 4 cancers (2 BCC and 2 SCC). The odds of developing at least one skin cancer was significantly lower with nicotinamide (odds ratio=0.14) as was the rate of new skin cancers (relative rate=0.24..) . and adjusting for study and number of previous skin cancersAK counts at baseline and follow-up are shown in the Table 1. A 35% relative reduction in AK count at 4 months was estimated from Study 1 (with similar results at 2 months). A 29% relative reduction in AK count at 4 months..was estimated from Study 2 (with smaller but significant differences observed at 2 months). There was no evidence that the relative effect of nicotinamide was modified by baseline AK count 500
https://pubmed.ncbi.nlm.nih.gov/38593249/4Human study - adjunctAfter a median follow-up of 54.3 months, the nicotinamide group exhibited a median PFS of 12.7 months , while the placebo group had a PFS of 10.9 months.. The median OS was similar in the two groups (31.0 months with nicotinamide vs. 29.4 months with placebo; P = 0.2). Notably, subgroup analyses revealed a significant reduction in mortality risk for females and never-smokers treated with nicotinamide.We assessed the impact of nicotinamide on carcinogen-induced lung adenocarcinomas in mice and observed that nicotinamide increased RUNX3 levels and inhibited lung cancer growth. Subsequently, 110 consecutive patients with stage IV lung cancer who had EGFR mutations were recruited: 70 females (63.6%) and 84 never-smokers (76.4%). The patients were randomly assigned to receive either nicotinamide (1 g/day, n = 55) or placebo (n = 55). The primary and secondary endpoints were progression-free survival (PFS) and overall survival (OS), respectively.
https://cancerci.biomedcentral.com/articles/10.1186/s12935-023-02860-73.5Meta-analysishe levels of VitB3 were statistically significant between the healthy control group and the breast cancer group (P = 0.047 after adjustment), and between the breast benign disease group and the breast cancer group The levels of VitB1 and VitB5 in the serum of breast cancer patients and patients with benign breast diseases were higher than those in the healthy control group, while the expression levels of VitB3 in breast cancer patients were lower than those in the healthy control group and the breast benign disease groups. The level of VitB1 was positively correlated with breast cancer risk. The VitB3 level was negatively correlated with breast cancer risk. The VitB5 level is not significantly related to the risk of breast cancer.
https://ascopubs.org/doi/10.1200/JCO.2010.28.49503.5Human study - adjunctMedian OS was 30 months in the control arm and 54 months in the experimental arm. Among the possible prognostic factors tested in the multivariate model, only hemoglobin concentration and treatment arm were significant (Table 3). At 3 years, there was a 13% improvement in OS in favor of radiotherapy plus carbogen and nicotinamide with a 14% lower risk of death and an 11% nonsignificant increase in RFSThe impact of radiotherapy plus carbogen and nicotinamide could be enhanced further by the addition of a radiosensitizer drug, like cisplatin, with a different mechanism of action and target cell population to that of hypoxia modification. The maximum impact will be seen in tumors in which hypoxia persists throughout treatment; translational research linked to the BCON trial is currently investigating the predictive ability of a hypoxia-associated gene signature. Trials comparing this regimen with other forms of chemoradiotherapy are now warranted.
https://aacrjournals.org/clincancerres/article-abstract/30/8/1478/742127/Nicotinamide-in-Combination-with-EGFR-TKIs-for-the?redirectedFrom=fulltext3.5Human studyThe addition of nicotinamide with EGFR-TKIs demonstrated potential improvements in PFS and OS, with notable survival benefits for female patients and those who had never smoked RUNX3 is a tumor suppressor gene, which is inactivated in approximately 70% of lung adenocarcinomas. Nicotinamide, a sirtuin inhibitor, has demonstrated potential in re-activating epigenetically silenced RUNX3 in cancer cells. This study assessed the therapeutic benefits of combining nicotinamide with first-generation EGFR–tyrosine kinase inhibitors (TKI) for patients with stage IV lung cancer carrying EGFR mutations.
https://ijmio.com/high-dose-nicotinamide-a-histone-deacetylase-inhibitor-sirtuin-1-can-prevent-emergence-of-treatment-resistance-in-chronic-myeloid-leukemia-a-perspective/3Lab studyWe need to study in detail nicotinamide and its role in addition to the conventional treatment of TKI in CML. Nicotinamide and its inhibitory action on SIRT-1 will help in eliminating quiescent stem cells. These quiescent stem cells are responsible for drug resistance and disease progression. It has been proven that histone deacetylase inhibitors help in annihilating these quiescent stem cells. Thus, we suggest nicotinamide, in addition to conventional TKIs, be added to the treatment armamentarium to prevent the emergence of resistance to TKI.Hence, nicotinamide, an amide derivative of Vitamin B3, also has myriads of effects to potentiate the effect of TKIs apart from itself having anti-leukemia activity as far as BCR-ABL inhibition is concerned. It also increased the sensitivity of doxorubicin and reduced its cardiotoxicity in one of the published studies on CML cell lines.[5] Nicotinamide is a non-competitive inhibitor of SIRT-1.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9067146/3Lab studyNAM leads to bifurcating metabolic alterations (RET and lipogenic pathways) in TNBC and promotes the ROS‐induced apoptotic pathway. Moreover, our combined preclinical analysis with in‐vivo and ex‐vivo models is the first to show that NAM significantly suppresses tumour growth and metastasis in TNBC. We believe that future studies should include clinical trials of NAM by involving TNBC patients to determine the efficacy of NAM supplementation and optimize the dose of NAM in the clinical settingThe doses used for treating animals are compatible with 80 or 160 mg·kg−1 for humans, which are two to three times higher than those reported previously [56]. However, we targeted highly aggressive mammary carcinoma that might require a higher dose of the drug compared with what is required for maintaining general physiological functions. An additional validation test with a patient‐derived organoid model also showed similar therapeutic efficacy of NAM in TNBC. Although there may be a considerable gap between organoids and the human environment, patient‐derived organoids are an excellent preclinical model that provides a platform for the evaluation of drug response in breast cancerScreenshot from 2024-03-30 13-02-201000
https://www.science.org/doi/abs/10.1126/scitranslmed.ade33413Human study - adjunctWe also conducted a first-in-human phase 1 clinical trial testing adoptive transfer of NK cells expanded ex vivo with IL-15 and NAM (GDA-201) combined with monoclonal antibodies in patients with relapsed or refractory non-Hodgkin lymphoma (NHL) and multiple myeloma (MM) (NCT03019666). Cellular therapy with GDA-201 and rituximab was well tolerated and yielded an overall response rate of 74% in 19 patients with advanced NHL. Thirteen patients had a complete responseNAM promoted the stability of FOXO1 by preventing proteasomal degradation. NK cells cultured with NAM exhibited metabolic changes associated with elevated glucose flux and protection against oxidative stress. NK cells incubated with NAM also displayed enhanced cytotoxicity and inflammatory cytokine production and preferentially persisted in xenogeneic adoptive transfer experiments
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3582128/3Lab studySpecific enhancement of mitochondrial complex I activity inhibited tumor growth and metastasis through regulation of the tumor cell NAD+/NADH redox balance, mTORC1 activity, and autophagy. Conversely, nonlethal reduction of NAD+ levels by interfering with nicotinamide phosphoribosyltransferase expression rendered tumor cells more aggressive and increased metastasis. The results translate into a new therapeutic strategy: enhancement of the NAD+/NADH balance through treatment with NAD+ precursors inhibited metastasis in xenograft models, increased animal survival, and strongly interfered with oncogene-driven breast cancer progression in the MMTV-PyMT mouse modelThe present study demonstrated that mitochondrial complex I regulation of tumor cell NAD+/NADH levels affects breast cancer growth and metastasis and translated into a new therapeutic approach for preventing breast cancer progression. This is highly relevant, as the current standard of care for cancer patients relies primarily on chemo- and radiation therapies aimed at killing the tumor cells. Evolutionary models predict that selective pressure imposed by these approaches causes survival of resistant clones that eventually reactivate the disease (61). Based on the central involvement of metabolic tumor cell alterations in cancer, therapeutic normalization of tumor cell metabolism might interfere with the expansion of residual and breakthrough clones. Thus, a combination of standard therapy with NAD+ precursor treatment may halt breast cancer progression and prevent relapse.Screenshot from 2024-03-30 13-18-24
https://www.scielo.br/j/abd/a/JGdgg6vQbvcBZnZgqtbFxZd/?lang=en3Human study - adjunctThere was a change in Ki67 expression with both treatments, with a significant difference in the nicotinamide group. Thus, although there is no additional clinical response of nicotinamide to the treatments implemented in this study, there is evidence of a reduction in cellular proliferation.10 Longer nicotinamide regimens might lead to more robust clinical outcomesIn conclusion, the efficacy of the treatment of SFC with topical 5FU, using an intermittent regimen for 120 days was evidenced. The present study results should stimulate clinical trials with topical 5FU using an intermittent regimen to explore its role in SFC stabilization, reducing the incidence of AKs and skin neoplasms
https://www.nejm.org/doi/full/10.1056/NEJMoa2203086N/A
https://link.springer.com/article/10.1007/s00394-024-03425-83Meta-analysisNiacin treatment is associated with significant reductions in CRP and TNF-α levels, suggesting potential anti-inflammatory effects. Additionally, niacin positively influences adipokines, increasing Adiponectin and Leptin levels. These findings provide insights for future research and clinical applications targeting inflammation and metabolic dysregulation.fifteen randomized controlled trials (RCTs) were included. Niacin administration demonstrated a notable reduction in CRP levels (SMD: -0.88, 95% CI: -1.46 to -0.30, p = 0.003). Subgroup analyses confirmed CRP reductions in trials with intervention durations ≤ 24 weeks, doses ≤ 1000 mg/day, and elevated baseline CRP levels (> 3 mg/l). The meta-analysis of IL-6 and TNF-α revealed significant TNF-α reductions, while IL-6 reduction did not reach statistical significance. Niacin administration also substantially elevated Adiponectin (SMD: 3.52) and Leptin (SMD: 1.9) levels.

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