Cisplatin-Induced Kidney Toxicity: Potential Roles of Major NAD+-Dependent Enzymes and Plant-Derived Natural Products

Abstract

Cisplatin is an FDA approved anti-cancer drug that is widely used for the treatment of a variety of solid tumors. However, the severe adverse effects of cisplatin, particularly kidney toxicity, restrict its clinical and medication applications. The major mechanisms of cisplatin-induced renal toxicity involve oxidative stress, inflammation, and renal fibrosis, which are covered in this short review. In particular, we review the underlying mechanisms of cisplatin kidney injury in the context of NAD+-dependent redox enzymes including mitochondrial complex I, NAD kinase, CD38, sirtuins, poly-ADP ribosylase polymerase, and nicotinamide nucleotide transhydrogenase (NNT) and their potential contributing roles in the amelioration of cisplatin-induced kidney injury conferred by natural products derived from plants. We also cover general procedures used to create animal models of cisplatin-induced kidney injury involving mice and rats. We highlight the fact that more studies will be needed to dissect the role of each NAD+-dependent redox enzyme and its involvement in modulating cisplatin-induced kidney injury, in conjunction with intensive research in NAD+ redox biology and the protective effects of natural products against cisplatin-induced kidney injury.

Renal-Protective Roles of Lipoic Acid in Kidney Disease

“…Cisplatin is a chemotherapy drug that treats cancer by entering the tumor cells, releasing chloride ions, and becoming hydrated to crosslink with DNA and form DNA adducts to inhibit tumor cell replication [ 97 , 98 ]. However, cisplatin medication has many side effects, such as ototoxicity, neurotoxicity, nephrotoxicity, nausea, and vomiting [ 35 , 97 , 98 , 99 ].…”

“…Cisplatin is a chemotherapy drug that treats cancer by entering the tumor cells, releasing chloride ions, and becoming hydrated to crosslink with DNA and form DNA adducts to inhibit tumor cell replication [ 97 , 98 ]. However, cisplatin medication has many side effects, such as ototoxicity, neurotoxicity, nephrotoxicity, nausea, and vomiting [ 35 , 97 , 98 , 99 ]. Nephrotoxicity occurs because cisplatin is taken up by the proximal tubular cells and can concentrate up to five times more than the cisplatin in the serum [ 35 , 97 ].…”

“…However, cisplatin medication has many side effects, such as ototoxicity, neurotoxicity, nephrotoxicity, nausea, and vomiting [ 35 , 97 , 98 , 99 ]. Nephrotoxicity occurs because cisplatin is taken up by the proximal tubular cells and can concentrate up to five times more than the cisplatin in the serum [ 35 , 97 ]. Cisplatin nephrotoxicity leads to decreased creatinine clearance, increased serum creatinine levels, increased urea levels, increased urine output, and decreased glomerular filtration rate [ 100 , 101 ].…”

Nicotinamide Mononucleotide Versus Nicotinamide Riboside in The Protective Effects of Cisplatin-induced DNA Damage in HeLa Cells

“…NAD + is important in maintaining cellular redox status, and cisplatin is also able to decrease NAD + level (12). Both NMN and NR can replenish cellular NAD + levels, but whether they can restore NAD + levels in cisplatin-treated cells was still not clearly documented.…”

Deletion of NADPH oxidase 2 attenuates cisplatin-induced acute kidney injury through reducing ROS-induced proximal tubular cell injury and inflammation

“…Overexpression of organic cation transporter 2 in human proximal tubular cells enhances cisplatin uptake and increases the risk of toxicity ( 5 ). Cisplatin uptake into renal tubular cells causes proximal tubular cell toxicity, mitochondrial dysfunction, DNA damage, and decreased antioxidant glutathione levels, leading to the accumulation of reactive oxygen species (ROS) ( 6 , 7 ). ROS are important in maintaining normal kidney gluconeogenesis, electrolyte transport, glucose transport, and hemodynamics ( 8 ).…”