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Over the past few years, a growing body of experimental observations has led to the identification of novel and alternative programs of regulated cell death. Recently, autophagic cell death and controlled forms of necrosis have emerged as major alternatives to apoptosis, the best characterized form of regulated cell demise. These recently identified, caspase-independent, forms of cell death appear to play a role in the response to several forms of stress, and their importance in different pathological conditions such as ischemia, infection and inflammation has been recognized. The functional link between cell metabolism and survival has also been the matter of recent studies. Nicotinamide adenine dinucleotide (NAD(+)) has gained particular interest due to its role in cell energetics, and as a substrate for several families of enzymes, comprising poly ADP-ribose polymerases (PARPs) and sirtuins, involved in numerous biological functions including cell survival and death. The recently uncovered diversity of cell death programs has led us to reevaluate the role of this important metabolite as a universal pro-survival factor, and to discuss the potential benefits and limitations of pharmacological approaches targeting NAD(+) metabolism., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Increasing evidence indicates that cancer cells rewire their metabolism during tumorigenesis. The high intracellular levels of lactate and reactive oxygen species (ROS) generated during enhanced aerobic glycolysis and mitochondrial oxidative phosphorylation respectively led to oxidative stress. The detoxification of these accumulating metabolites and the equilibrium between reduced and oxidized nicotine adenine dinucleotide (NADH and NAD(+)) are two prominent mechanisms regulating redox status and hence energy homeostasis in tumors. Targeting both processes may thus be selectively cytotoxic for cancer cells. In this context, the impact of poly(ADP-ribose) polymerase (PARP) inhibitors, a class of anticancer agents employed for the treatment of DNA repair deficient tumors, on energy homeostasis and mitochondrial respiration regulation has potential clinical implications. Here we provide an overview of the metabolic reprogramming occurring in cancer cells and discuss the translational perspectives of targeting tumor metabolism and redox balance for antineoplastic therapy., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Activation of poly(ADP-ribose)polymerase by DNA damaging agents causes a depletion of intracellular NAD+ and subsequent lowering of ATP pools, which if extensive may lead to cell death. We have studied the cytotoxicity to isolated hepatocytes of dimethyl sulphate, a direct-acting carcinogen and mutagen, hydrogen peroxide, generated by glucose/glucose oxidase, and menadione (2-methyl-1,4-naphthoquinone) in relation to their effects on intracellular NAD+ and ATP levels. Both dimethyl sulphate and glucose/glucose oxidase caused a depletion of NAD+, which was apparently due to an activation of poly(ADP-ribose)polymerase as it was prevented by inhibitors of the polymerase, i.e. 3-aminobenzamide and nicotinamide. This protection of intracellular NAD+ was accompanied by a prevention of the cytotoxicity of both dimethyl sulphate and glucose/glucose oxidase, while it did not alter the decrease in intracellular ATP they induced. This apparent dissociation of effects on ATP from NAD+ does not support the suggestion that activation of poly(ADP-ribose)polymerase leads to a decrease in cellular ATP as a consequence of NAD+ depletion. Menadione also caused a depletion of NAD+ which preceded cytotoxicity, but in contrast to dimethyl sulphate and H2O2 this depletion did not involve poly(ADP-ribose)polymerase as it was not prevented by inhibitors of the enzyme. Our results also indicate that the cytotoxicity of menadione is not mediated by H2O2 alone. Marked depletion of intracellular NAD+ prior to toxicity and a protection against toxicity associated with maintenance of NAD+ suggest a possible role for the maintenance of intracellular NAD+ in cellular integrity.

It is rapidly becoming accepted, without direct evidence, that a change in the NAD+/NADH ratio in the testes produced by the metabolism of ethanol is the principal mechanism involved in its now well-established effects on testicular steroidogenesis. The purposes of the present studies were 2-fold: (1) to examine whether, in fact, in vivo or in vitro ethanol exposure alters the NAD+/NADH ratio in the testes; and (2) to examine the validity of previous reports in which it was found that NAD+ prevented the effects of ethanol on testicular steroidogenesis under in vitro conditions. With regard to the first objective, we found that a large dose of ethanol (2.5 g/kg) markedly reduced gonadotropin-stimulated testicular steroidogenesis in vivo in the male rat, but it did not alter the NAD+ and NADH concentrations in the testes. Similarly, extremely high ethanol concentrations (200 mM) substantially suppressed hMG-stimulated testosterone biosynthesis in in vitro Leydig cell preparations but no change in NAD+ concentration occurred; NADH levels were very low in the Leydig cell preparations (less than 2% of NAD+ levels), but did not appear to change as a function of ethanol exposure. Finally, in contrast to previously published results, we found that NAD+ (1 mM) did not prevent the in vitro effects of ethanol on cAMP-stimulated testicular steroidogenesis. Consequently, our results fail to support the hypothesis that acute in vivo or in vitro ethanol administration inhibits the biosynthesis of testosterone by altering the NAD+/NADH ratio in the testes.