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T here are now extensive scientific data suggesting the potential role of dietary and non-dietary phytochemicals in the prevention and control of prostate cancer (PCA) growth and progression. PCA is a disease of elderly male populations with a relatively slower rate of growth and progression as compared to most other cancers and, therefore, is a candidate disease for preventive intervention. Overall, PCA growth and progression involve aberrant mitogenic and survival signaling and deregulated cell cycle progression, accompanied by gradual accumulation of genetic and epigenetic changes over a period of years. Several mechanisms, including overexpression of growth, survival and angiogenic factors and their receptors, together with a loss/decrease of tumor suppressor p53, retinoblastoma and cyclin-dependent kinase inhibitor, have been implicated in PCA growth and progression. Therefore, phytochemicals targeting these molecular events could have a promising role in PCA prevention and/or therapy. Inositol hexaphosphate (IP6) is a major constituent of most cereals, legumes, nuts, oil seeds and soybean. Taken orally as an over-the-counter dietary/nutrient supplement, and is recognised as offering several health benefits without any known toxicity. In vitro anticancer efficacy of IP6 has been observed in many human, mouse and rat prostate cancer cells. Completed studies also show that oral feeding of IP6 inhibits human PCA xenograft growth in nude mice without toxicity. In a recently completed pilot study, we observed similar preventive effects of IP6 on prostate tumorigenesis in the TRAMP model. Mechanistic studies indicate that IP6 targets mitogenic and survival signaling, as well as cell cycle progression, in PCA cells. IP6 is also shown to target molecular events associated with angiogenesis. Moreover, IP6 has pleiotropic molecular targets for its overall efficacy against PCA and, therefore, could be a suitable candidate agent for preventive intervention of this malignancy in humans.

NAD+, a vital metabolite and co-enzyme, exists in two primary states within cells: oxidized (NAD+) and reduced (NADH), both crucial for metabolic processes like glycolysis, the tricarboxylic acid (TCA) cycle, and the electron transport chain (ETC). NAD+ is essential for the enzymatic activities that drive post-translational modifications, including those catalyzed by sirtuins such as SIRT1 and ADP-ribosyltransferases (PARPs). Particularly, SIRT1 regulates basal metabolism by deacetylating key metabolic regulators, while PARP1, under DNA damage, consumes NAD+ significantly, impacting cellular viability due to ATP depletion.

Aging triggers chronic DNA damage and subsequent PARP activation, leading to NAD+ depletion and mitochondrial dysfunction, which can be counteracted by NAD+ precursors like nicotinamide mononucleotide (NMN). Additionally, PARP1 inhibitors can enhance mitochondrial function by raising cellular NAD+ levels. Cellular NAD+ is maintained through three synthesis pathways: the de novo pathway from tryptophan in the liver, the Preiss–Handler pathway from nicotinic acid, and the salvage pathway from nicotinamide riboside (NR) or nicotinamide (NAM). Fluctuations in NAD+ levels have significant cellular impacts, with emerging evidence suggesting NAD+ can traverse cellular membranes via specific transport proteins, impacting mitochondrial function and DNA synthesis directly.

In experimental studies, altering NAD+ levels through inhibition of PARP1, SIRT1, and NAMPT affected DNA synthesis across various cell models. PARP inhibition consistently reduced DNA synthesis, while NAMPT inhibition had a pronounced effect in HeLa cells, significantly reducing intracellular NAD(H) levels. The study extended to measuring DNA synthesis and DNA damage response (DDR) activation, finding that NAMPT inhibition decreased DNA synthesis in HeLa cells without affecting U2OS cells, and that PARP1 inhibition reduced DNA synthesis globally and triggered DDR. Analyses using the DNA fibre technique further quantified replication fork dynamics, revealing that PARP1 inhibition could enhance fork progression and activate DDR. This comprehensive study underscores the complex role of NAD+ in regulating mitochondrial function, DNA replication, and cell proliferation, proposing a nuanced model of NAD+ action within cellular and genomic contexts.

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