NAD+ metabolism, sternness, the immune response, and cancer

NAD+was discovered during yeast fermentation,and since its discovery,its important roles in redox metabolism,aging,and longevity,the immune system and DNA repair have been highlighted.A deregulation of the NAD+levels has been associated with metabolic diseases and aging-related diseases,including neurodegeneration,defective immune responses,and cancer.NAD+acts as a cofactor through its interplay with NADH,playing an essential role in many enzymatic reactions of energy metabolism,such as glycolysis,oxidative phosphorylation,fatty acid oxidation,and the TCA cycle.NAD+also plays a role in deacetylation by sirtuins and ADP ribosylation during DNA damage/repair by PARP proteins.Finally,different NAD hydrolase proteins also consume NAD+while converting it into ADP-ribose or its cyclic counterpart.Some of these proteins,such as CD38,seem to be extensively involved in the immune response.Since NAD cannot be taken directly from food,NAD metabolism is essential,and NAMPT is the key enzyme recovering NAD from nicotinamide and generating most of the NAD cellular pools.Because of the complex network of pathways in which NAD+is essential,the important role of NAD+and its key ge nerating enzyme,NAMPT,in cancer is understandable.In the present work,we review the role of NAD+and NAMPT in the ways that they may influence cancer metabolism,the immune system,stemness,aging,and cancer.Finally,we review some ongoing research on therapeutic approaches.

Sarcoma stratification by combined pH2AX and MAP17(PDZK1IP1)levels for a better outcome on doxorubicin plus olaparib treatment

Sarcomas constitute a rare heterogeneous group of tumors,including a wide variety of histological subtypes.Despite advances in our understanding of the pathophysiology of the disease,first-line sarcoma treatment options are still limited and new treatment approaches are needed.Histone H2AX phosphorylation is a sensitive marker for double strand breaks and has recently emerged as biomarker of DNA damage for new drug development.In this study,we explored the role of H2AX phosphorylation at Ser139 alone or in combination with MAP17 protein,an inducer of DNA damage through ROS increase,as prognostic biomarkers in sarcoma tumors.Next,we proposed doxorubicin and olaparib combination as potential therapeutic strategies against sarcomas displaying high level of both markers.We evaluate retrospectively the levels of pH2AX(Ser139)and MAP17 in a cohort of 69 patients with different sarcoma types and its relationship with clinical and pathological features.We found that the levels of pH2AX and MAP17 were related to clinical features and poor survival.Next,we pursued PARP1 inhibition with olaparib to potentiate the antitumor effect of DNA damaging effect of the DNA damaging agent doxorubicin to achieve an optimal synergy in sarcoma.We demonstrated that the combination of olaparib and doxorubicin was synergistic in vitro,inhibiting cell proliferation and enhancing pH2AX intranuclear accumulation,as a result of DNA damage.The synergism was corroborated in patient-derived xenografts(PDX)where the combination was effective in tumors with high levels of pH2AX and MAP17,suggesting that both biomarkers might potentially identify patients who better benefit from this combined therapy.