Cisplatin is one of the most widely used broad-spectrum anticancer agents, and is used for the treatment of various solid tumors such as ovarian cancer, prostate cancer, bladder cancer, head or neck cancer, and lung cancer ^[1][2][1,2]. The antitumor mechanisms of cisplatin are mainly DNA damage via the enhanced generation of reactive oxygen species (ROS) [3]. The excess ROS such as superoxide anion, hydrogen peroxide, and hydroxyl radical would cause oxidative damage to various important molecules including proteins, lipids, and/or DNAs, leading to the critical damage of cancer cells [4]. It had been suggested that hydrogen peroxide is involved in the cisplatin-induced necrosis, whereas hydroxyl radical is responsible for the cisplatin-induced apoptosis [5]. Accordingly, the protective effects of hydroxyl radical scavengers are associated with an inhibition of cytochrome c release and caspase activation [5]. In general, cancer cells have higher levels of ROS than normal cells as a result of hyper-metabolism [6]. In addition to their extreme cytotoxicity, cisplatin could also have a variety of non-specific adverse reactions in cancer patients [7]. Studies have suggested that the accumulation of intracellular ROS is a hallmark of cisplatin-induced acute kidney injury (AKI) [8]. Cisplatin may show high activity in the fast proliferating cells, thereby causing cellular damage. In particular, about 30% of cisplatin-administered patients suffer from renal dysfunction and/or injury [9]. Increased formation of ROS in renal proximal convoluted tubule cells may be associated with the cisplatin-induced AKI [10], which is a substantial complication of cisplatin chemotherapy related to the ROS-dependent death of renal cells [11]. The AKI may be associated with high morbidity and mortality. To date, there are few strategies for preventing cisplatin-induced AKI [12], and it is urgent to search for novel therapeutic procedures to protect the kidney against the nephrotoxicity of cisplatin. In recent years, remarkable advances have been made in effective protective regimens for the nephrotoxicity of cisplatin [13]. Basically, protection of kidney from cisplatin-induced AKI might be attainable with antioxidant-based therapeutic interventions that increase antioxidant levels and thus improve the damage from ROS.

2. ROS and Autophagy in Cisplatin-Induced Acute Kidney Injury

The excessive generation of ROS has been regarded as the critical role during the pathogenetic process induced by cisplatin, by which DNA damage and/or cell death could occur. Increased ROS production is also known to change the mitochondrial electron transport chain, and eventually lead to apoptosis ^[14][19]. In particular, the dysfunction of the mitochondrial respiratory chain results in the further excess production of ROS that contributes to severe kidney injury ^[15][20]. Consequently, the mitochondrial dysfunction induced by the treatment with cisplatin could be considered as due to increased levels of ROS resulting in various cellular apoptosis including kidney cells ^[2][16][2,21]. Increased levels of ROS can also contribute to the tubular cell apoptosis in kidney, thereby causing more severe kidney injury during AKI ^[17][22]. Further generation of ROS in the tubular cells mitochondria might thus possibly contribute to the exacerbation of cisplatin-induced AKI. Therefore, the elimination of ROS has long been considered as an effective procedure to prevent the cisplatin-induced AKI ^[18][23]. In addition to increased ROS levels, treatment with cisplatin also impairs the activity of antioxidants such as superoxide dismutases (SODs), catalase, and glutathione peroxidase, which could function to reduce ROS levels ^[19][24]. The SODs are ROS-eliminating super enzymes with several subcellular localizations ^[20][25]. Targeting the cisplatin-induced oxidative stress via manipulation of the cellular antioxidant system including the expression of SODs could be beneficial for protecting against cisplatin nephrotoxicity. In fact, some agents with antioxidant and/or anti-inflammation activities could alleviate the cisplatin-induced cell damage by reduced production of ROS ^[21][26]. These therapeutic approaches may enhance the tolerance to cisplatin and hence might enable greater dose intensity associated with better outcomes. It has been shown that sirt1 expression on proximal tubules in the kidney may save cisplatin-induced AKI by preserving the function of peroxisomes and the elimination of ROS, which could be a potential therapeutic target for the treatment of cisplatin-induced AKI ^[22][27] (Figure 1). ROS-induced autophagy may also lead to a different outcome of cell fate that may result in cell survival or cell death, depending on the severity of ROS exposure ^[23][28]. ROS impact on autophagy is mediated by specific signaling pathways, which might reduce the oxidative damage by degrading and/or recycling intracellular oxidized macromolecules and dysfunctional organelles ^[24][29].

3. Autophagy as a Target for the Treatment of Cisplatin-Induced Acute Kidney Injury

Autophagy, a highly conserved multistep catabolic pathway in eukaryotic cells, degrades and/or recycles macromolecules and/or dysfunctional organelles, which also contributes to the maintenance of the homeostasis of the kidney. For example, an inducer of autophagy could protect cells in an autophagy dependent manner ^[25][34]. In addition, the activity of autophagy regulator beclin 1 brings kidney protection via the reduction of kidney damage, subsequently refining kidney recovery post-AKI ^[26][35]. The beneficial effect of autophagy has a potential clinical significance in minimizing or preventing cisplatin nephrotoxicity ^[27][36]. In fact, autophagy occurs in AKI, and this might be an imperative mechanism for protection of cell survival ^[28][37]. Autophagy can protect kidney proximal tubules against AKI, possibly by alleviating DNA damage and/or ROS production ^[29][30][33,38]. In general, adenosine-monophosphate activated-protein kinase (AMPK) and mammalian target of rapamycin (mTOR) are major positive and negative regulators of autophagy, respectively. Therefore, inhibition of AMPK could lead to autophagy in cisplatin-induced AKI, resulting in more cellular or tubular kidney damage ^[31][39]. It has been indicated that penicilliumin-B denotes a different AMPK activator that might provide considerable protection against the apoptosis of renal tubular cells through the activated AMPK-induced autophagy and/or mitochondrial regeneration ^[32][40]. Likewise, metformin might protect against the cisplatin-induced apoptosis of tubular cells and/or AKI through stimulating AMPK-activation and/or inducing autophagy ^[33][41]. In addition, it has been shown that the pre-activation of autophagy could improve the survival and differentiation of kidney cells by inhibiting the mTOR signaling pathway, which in turn could mitigate the cisplatin-induced AKI ^[34][42]. In this regard, various compounds have an impact on the autophagy within kidney diseases. For example, chlorogenic acids may decrease cisplatin-induced AKI through alterations of inflammation, oxidative stress, apoptosis and/or autophagy, with the improvement in kidney restoration ^[35][43]. Also, ginsenoside effectively protects against cisplatin-induced AKI by activating the autophagy-mediated pathway ^[36][44]. The ginsenoside mediated improvement has been found due to the regulation of AMPK and/or mTOR-mediated autophagy and the inhibition of apoptosis ^[37][45]. Autophagy-mediated inhibition of apoptosis might also play a crucial role in astragaloside-mediated protection against cisplatin-induced renotoxicity ^[38][46]. In addition, berberine could play a protecting role in cisplatin-induced AKI by up-regulating mitophagy that is a kind of autophagy ^[39][47]. Similarly, Pink1 or Parkin dependent mitophagy has also identified potential targets for the treatment of cisplatin-induced AKI ^[40][48]. Honokiol treatment may cause noticeable kidney protection and attenuation of the cisplatin-induced kidney changes via preventing mitochondrial dysfunction ^[41][49]. Morin hydrate, a natural flavonoid, could also improve autophagy and/or inflammatory responses and decrease the cellular death in kidney, suggesting morin hydrate as a potential therapeutic agent against cisplatin-induced nephrotoxicity ^[42][50]. Trehalose treatment similarly conserves mitochondrial function via the activation of autophagy, and then attenuates cisplatin-induced AKI ^[43][51]. Cordyceps cicadae, a traditional Chinese medicine, may have a potential kidney protective effectfor prevention of cisplatin-induced AKI through the inhibition of various oxidative stresses by activating AMPK ^[44][52]. It is reported that treatment with 3-dehydroxyceanothetric acid 2-methyl ester isolated from the root of Ziziphus jujuba has decreased the autophagic vesicles via the altered protein expressions of AMPK and/or mTOR dependent pathway against cisplatin-induced AKI ^[45][53]. Retinoic acids could also improve cisplatin-induced AKI through the activation of autophagy, and the retinoic acids might have some protective effects for cisplatin-based chemotherapy ^[46][54]. AMPK activation is probably essential for the protection of kidney via the lithium-induced tubular cell autophagy in cases of cisplatin-induced AKI ^[47][55]. In addition, IFN-γ could accelerate autophagic change in kidney and increase the viability of kidney tubular cells, thereby attenuating cisplatin-induced AKI ^[48][56]. Deficiency of neutral ceramidase, an enzyme responsible for converting ceramide into sphingosine, could protect against cisplatin-induced AKI by the mechanism of increased autophagy ^[49][57]. Amniotic fluid stem cells may lead to amelioration of cisplatin-induced AKI, which is mediated by inhibition of apoptosis and/or activation of autophagy ^[50][58]. However, persistent autophagy after AKI induces pro-fibrotic cytokines in renal tubular cells, promoting renal fibrosis and chronic kidney disease (CKD) ^[51][59]. As described above, autophagy is deeply involved in the cisplatin-induced AKI, and autophagy could be a target for kidney protection.