I just did a post on how cysteine (a reductant and glutathione precursor) is therapeutic for an aggressive form of breast cancer. Another post, just a few hours ago, showed that niacin treatment may be therapeutic precisely for brain cancer (glioblastoma) and as such the treatment is in Phase II human clinical trials. While the studies with niacin claim that its benefit was based on niacin sensitizing cancer cells to chemotherapy and radiation, while also increasing immune cell activity (T-cells). However, I think this explanation is deliberately misleading in order to conceal the fact that vitamin B3 (in that case, niacin) has pro-metabolic effects that are known to be therapeutic for cancer, even when vitamin B3 is used as the main therapy and not as an adjuvant. While most of the studies that used vitamin B3 for cancer have so far focused on the role of this vitamin as an NAD+ precursor thus restoring mitochondrial NAD+ levels known to be depleted in cancer, the study below describes another beneficial mechanism of vitamin B3, in this case niacinamide. Namely, higher niacinamide levels are known to saturated the NAD+ synthesizing enzyme NAMPT and the excess niacinamide is converted into N1-methylnicotinamide by gaining a methyl group from the amino acid methionine. Thus, excess niacinamide serves as a methyl sink and consumes methionine, thus mimicking methionine restriction/deficiency. Methionine has a known role as a potent metabolic inhibitor and studies with methionine restriction have demonstrated multiple health benefits such as reversal of obesity (including in humans), amelioration of diabetes, aging, and even extension of (maximum) lifespan. Thus, the findings of the study below that methionine depletion through dietary restriction and/or excess niacinamide once again underscores the nature of cancer as metabolic disease.
https://pmc.ncbi.nlm.nih.gov/articles/PMC12829581/
“…In tumors of patients with glioblastoma, NNMT outcompetes NAMPT, the enzyme responsible for NAD+ production, for nicotinamide (Fig. 3S). This form of vitamin B3 efficiently permeates the brain (Figs. 3, R and S, and 4, O and P) where the tumor-specific methyltransferase activity of NNMT introduces a positive charge on its pyridine ring. These findings provided a clear mechanistic rationale to design a nicotinamide-based PET tracer for the metabolic imaging of glioblastoma, which can be enhanced by the administration of dexamethasone (Fig. 5E). Our approach shows the feasibility of radiochemical synthesis of 11C-nicotinamide, and the imaging results demonstrate its suitability to visualize tumors in orthotopic models of glioblastoma (Fig. 5D), strengthening the case for clinical development of novel PET tracers based on vitamin B3 analogs. Last, we show that dexamethasone promotes the diversion of methionine-derived methyl groups toward N1-methylnicotinamide, sensitizing glioblastoma tumors to methionine restriction. Our results align with a recent report showing that methionine restriction diet as single treatment did not significantly decrease the levels of methionine and growth of another intracranial glioblastoma tumor model (39). Our working model, supported by evidence obtained in culture (Fig. 3, O to Q) and in vivo (Fig. 5, I to L), suggests that a methionine-restricted diet would synergize with the systemic rewiring of methionine metabolism imposed by dexamethasone, resulting in a brain-specific metabolic state with antitumor effects for glioblastoma (Fig. 5M). Given the scarcity of effective therapies for glioblastoma, we believe that these results achieved by combining dexamethasone, already a de facto standard of care for many patients with glioblastoma, with methionine restriction diet in a clinically relevant model represent a meaningful advance that warrants further exploration.”
