Cisplatin is one of the most widely used and highly effective drug for the treatment of various solid tumors; however, it has dose-dependent side effects on the kidney, cochlear, and nerves. Nephrotoxicity is the most well-known and clinically important toxicity. Numerous studies have demonstrated that several mechanisms, including oxidative stress, DNA damage, and inflammatory responses, are closely associated with cisplatin-induced nephrotoxicity. Even though the establishment of cisplatin-induced nephrotoxicity can be alleviated by diuretics and pre-hydration of patients, the prevalence of cisplatin nephrotoxicity is still high, occurring in approximately one-third of patients who have undergone cisplatin therapy. Therefore it is imperative to develop treatments that will ameliorate cisplatin-nephrotoxicity. In this review, we discuss the mechanisms of cisplatin-induced renal toxicity and the new strategies for protecting the kidneys from the toxic effects without lowering the tumoricidal activity.

Cisplatin is a widely used chemotherapeutic agent for the treatment of various tumors. In addition to its antitumor activity, cisplatin affects normal cells and may induce adverse effects, such as ototoxicity, nephrotoxicity, and neuropathy. Various mechanisms, such as DNA adduct formation, mitochondrial dysfunction, oxidative stress, and inflammatory responses, are critically involved in cisplatin-induced adverse effects. As NAD+ is a cofactor for various enzymes associated with cellular homeostasis, we studied the effects of increased NAD+ levels by means of NAD(P)H:quinone oxidoreductase 1 (NQO1) activation using a known pharmacological activator (β-lapachone) in wild-type and NQO1−/− mice on cisplatin-induced renal dysfunction in vivo. The intracellular NAD+/NADH ratio in renal tissues was significantly increased in wild-type mice co-treated with cisplatin and β-lapachone compared with the ratio in mice treated with cisplatin alone. Inflammatory cytokines and biochemical markers for renal damage were significantly attenuated by β-lapachone co-treatment compared with those in the cisplatin alone group. Notably, the protective effects of β-lapachone in wild-type mice were completely abrogated in NQO1−/− mice. Moreover, β-lapachone enhanced the tumoricidal action of cisplatin in a xenograft tumor model. Thus, intracellular regulation of NAD+ levels through NQO1 activation might be a promising therapeutic target for the protection of cisplatin-induced acute kidney injury.

Dysfunction in immune surveillance during anticancer chemotherapy of patients often causes weakness of the host defense system and a subsequent increase in microbial infections. However, the deterioration of organ-specific function related to microbial challenges in cisplatin-treated patients has not yet been elucidated. In this study, we investigated cisplatin-induced TLR4 expression and its binding to LPS in mouse cochlear tissues and the effect of this interaction on hearing function. Cisplatin increased the transcriptional and translational expression of TLR4 in the cochlear tissues, organ of Corti explants, and HEI-OC1 cells. Furthermore, cisplatin increased the interaction between TLR4 and its microbial ligand LPS, thereby upregulating the production of proinflammatory cytokines, such as TNF-α, IL-1β, and IL-6, via NF-κB activation. In C57BL/6 mice, the combined injection of cisplatin and LPS caused severe hearing impairment compared with that in the control, cisplatin-alone, or LPS-alone groups, whereas this hearing dysfunction was completely suppressed in both TLR4 mutant and knockout mice. These results suggest that hearing function can be easily damaged by increased TLR expression and microbial infections due to the weakened host defense systems of cancer patients receiving therapy comprising three to six cycles of cisplatin alone or cisplatin combined with other chemotherapeutic agents. Moreover, such damage can occur even though patients may not experience ototoxic levels of cumulative cisplatin concentration.

Cisplatin (cis-diaminedichloroplatinum-II) is an extensively used chemotherapeutic agent, and one of its most adverse effects is ototoxicity. A number of studies have demonstrated that these effects are 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 a key regulator of cellular energy metabolism and homeostasis. Here, we demonstrate for the first time that, in cisplatin-mediated ototoxicity, the levels and activities of SIRT1 are suppressed by the reduction of intracellular NAD+ levels. We provide evidence that the decrease in SIRT1 activity and expression facilitated by increasing poly(ADP-ribose) transferase (PARP)-1 activation and microRNA-34a through p53 activation aggravates cisplatin-mediated ototoxicity. Moreover, we show that the induction of cellular NAD+ levels using β-lapachone (β-Lap), whose intracellular target is 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.

Hair cells at the base of the cochlea appear to be more susceptible to damage by the aminoglycoside gentamicin than those at the apex. However, the mechanism of base-to-apex gradient ototoxicity by gentamicin remains to be elucidated. We report here that gentamicin caused rodent cochlear hair cell damages in a time- and dose-dependent manner. Hair cells at the basal turn were more vulnerable to gentamicin than those at the apical turn. Gentamicin-conjugated Texas Red (GTTR) uptake was predominant in basal turn hair cells in neonatal rats. Transient receptor potential vanilloid 1 (TRPV1) and 4 (TRPV4) expression was confirmed in the cuticular plate, stereocilia and hair cell body of inner hair cells and outer hair cells. The involvement of TRPV1 and TRPV4 in gentamicin trafficking of hair cells was confirmed by exogenous calcium treatment and TRPV inhibitors, including gadolinium and ruthenium red, which resulted in markedly inhibited GTTR uptake and gentamicin-induced hair cell damage in rodent and zebrafish ototoxic model systems. These results indicate that the cytotoxic vulnerability of cochlear hair cells in the basal turn to gentamicin may depend on effective uptake of the drug, which was, in part, mediated by the TRPV1 and TRPV4 proteins.