Abstract
Melatonin is well known to modulate the sleep–wake cycle. Accumulating evidence suggests that melatonin also has favorable effects such as anti-oxidant and anti-inflammatory properties in numerous disease models. It has been reported that melatonin has therapeutic effects against cisplatin-induced acute kidney injury (AKI). However, mechanisms underlying the therapeutic action of melatonin on the renal side-effects of cisplatin therapy remain poorly understood. In this study, we showed that melatonin treatment significantly ameliorates cisplatin-induced acute renal failure and histopathological alterations. Increased expression of tubular injury markers was largely reduced by melatonin. Melatonin treatment inhibited caspase-3 activation and apoptotic cell death. Moreover, protein levels of key components of the molecular machinery for necroptosis were decreased by melatonin. Melatonin also attenuated nuclear factor-κB activation and suppressed expression of pro-inflammatory cytokines. Consistent with in vivo findings, melatonin dose-dependently decreased apoptosis and necroptosis in cisplatin-treated mouse renal tubular epithelial cells. Collectively, our findings suggest that melatonin ameliorates cisplatin-induced acute renal failure and structural damages through dual suppression of apoptosis and necroptosis. These results reveal a novel mechanism underlying the therapeutic effect of melatonin against cisplatin-induced AKI and strengthen the idea that melatonin might be a promising therapeutic agent for the renal side-effects of cisplatin therapy.
Highlights
Cisplatin is a platinum-based chemotherapy drug that has been used worldwide to treat various types of cancer
We examined whether melatonin could inhibit cisplatin-induced cell death in cultured TCMK-1 cells
We found that pretreatment with melatonin significantly reversed an increase in the number of TdT-Mediated dUTP Nick End Labeling (TUNEL)-stained cells after cisplatin treatment (Figure 7A,B)
Summary
Cisplatin is a platinum-based chemotherapy drug that has been used worldwide to treat various types of cancer. Its clinical use is frequently limited by severe adverse reactions including nephrotoxicity and hepatotoxicity [1,2]. 20% of patients treated with cisplatin suffer from nephrotoxicity such as acute kidney injury (AKI), while incidence of hepatotoxicity is lower [2,4]. Cisplatin-induced AKI is dose dependent and thereby limits the dose of drug that can be used [1]. Hepatotoxicity can occur only when cisplatin is administered at high doses [5]. Cisplatin-induced AKI is considered one of the major side-effects of cisplatin therapy. Some procedures including hydration management are used, there is still no specific pharmacotherapy for cisplatin-induced AKI
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