dunnione and Disease-Models--Animal

Cancer-associated thrombosis is the second-leading cause of mortality in patients with cancer and presents a poor prognosis, with a lack of effective treatment strategies. NAD(P)H quinone oxidoreductase 1 (NQO1) increases the cellular nicotinamide adenine dinucleotide (NAD

Topics: Animals; Breast Neoplasms; Cell Line, Tumor; Disease Models, Animal; Extracellular Traps; Female; Mice; Mice, Inbred BALB C; NAD; NAD(P)H Dehydrogenase (Quinone); Naphthoquinones; Sirtuin 1; Thrombophilia; Thromboplastin; Thrombosis

Topics: Animals; Antimalarials; Disease Models, Animal; HeLa Cells; Humans; Mice; Molecular Structure; Naphthoquinones; Quinone Reductases; Reactive Oxygen Species; Structure-Activity Relationship; Substrate Specificity

Ototoxicity is an important issue in patients receiving cisplatin chemotherapy. Numerous studies have demonstrated that cisplatin-induced ototoxicity is related to oxidative stress and DNA damage. However, the precise mechanism underlying cisplatin-associated ototoxicity is still unclear. The cofactor nicotinamide adenine dinucleotide (NAD(+)) has emerged as an important regulator of energy metabolism and cellular homeostasis. Here, we demonstrate that the levels and activities of sirtuin-1 (SIRT1) are suppressed by the reduction of intracellular NAD(+) levels in cisplatin-mediated ototoxicity. We provide evidence that the decreases in SIRT1 activity and expression facilitated by increasing poly(ADP-ribose) polymerase-1 (PARP-1) activation and microRNA-34a levels through cisplatin-mediated p53 activation aggravate the associated ototoxicity. Furthermore, we show that the induction of cellular NAD(+) levels using dunnione, which targets intracellular NQO1, prevents the toxic effects of cisplatin through the regulation of PARP-1 and SIRT1 activity. These results suggest that direct modulation of cellular NAD(+) levels by pharmacological agents could be a promising therapeutic approach for protection from cisplatin-induced ototoxicity.

Topics: Acetylation; Animals; Cisplatin; Cochlea; Cytoprotection; Disease Models, Animal; Hearing; Hearing Loss; Male; Mice, Inbred C57BL; Mice, Knockout; MicroRNAs; NAD; NAD(P)H Dehydrogenase (Quinone); Naphthoquinones; Poly (ADP-Ribose) Polymerase-1; Protective Agents; Signal Transduction; Sirtuin 1; Transcription Factor RelA; Tumor Necrosis Factor-alpha; Tumor Suppressor Protein p53