Abstract
Acute renal injury has an incidence of 25%–30% in patients with tumors who are treated with cisplatin and in patients for whom no specific drugs are available for treatment. Amifostine is the only FDA-approved chemoprotective drug; however, its clinical application is limited because of side effects. The small-molecule antioxidant XH-003, an acute radiation syndrome- (ARS-) protective drug independently developed in our laboratory, with 100% intellectual property rights, overcomes the side effects of amifostine but retains its high efficacy. In this study, XH-003 showed a chemoprotective effect similar to that of amifostine. A mechanistic study showed that XH-003 could significantly reduce cisplatin-induced increases in serum creatinine and urea nitrogen, increase the activity of antioxidant enzymes (SOD, CAT, and GSH-Px), reduce oxidative stress and tissue inflammation, and alleviate renal tissue damage by blocking the activity of the mitochondrial apoptosis pathway. Most importantly, XH-003 could reduce the accumulation of cisplatin in renal tissue by regulating the expression of proteins involved in cisplatin uptake and excretion, such as organic cation transporter 2 and MRP2. Moreover, in an in vivo xenotransplantation model, XH-003 did not interfere with the antitumor effect of cisplatin. These data provide strong evidence that the ARS-protective agent has a great potential for protecting against chemotherapy-induced toxicity. Thus, XH-003 can be considered in antitumor therapy.
Highlights
Cisplatin (DDP), a potent chemotherapeutic agent, is widely used to treat various types of solid tumors, such as bladder, cervical, head and neck, esophageal, triple-negative breast, and small-cell lung cancers [1,2,3]; it has severe side effects including ototoxicity, neurotoxicity, and nephrotoxicity
To establish a rat renal injury model suitable for our study, three doses of DDP were tested, and the results are shown in Figure 1 and Supplementary Table S1
Considering these factors, the optimal single dose of DDP of 5 mg/kg was applied to study the protective effect of XH-003 against DDP-induced nephrotoxicity
Summary
Cisplatin (DDP), a potent chemotherapeutic agent, is widely used to treat various types of solid tumors, such as bladder, cervical, head and neck, esophageal, triple-negative breast, and small-cell lung cancers [1,2,3]; it has severe side effects including ototoxicity, neurotoxicity, and nephrotoxicity. AKI is associated with preferential accumulation of DDP in renal tubules, resulting in renal dysfunction [5]. The detailed mechanism of DDP-induced AKI remains elusive. The proposed pathophysiological mechanisms of DDPinduced nephrotoxicity primarily involve DNA damage, the mitochondrial apoptosis pathway, inflammation, and oxidative stress [6,7,8]. Electrophilic compounds produced by DDP can interact with nuclear DNA and activate the p53 protein. DDP can interact with mitochondrial DNA, reduce the expression of electron transport chain proteins, damage respiration, and increase the production of reactive oxygen species (ROS). The increase in ROS can induce proinflammatory factors, resulting in inflammation. Inhibition of ROS by antioxidants is a potential approach to the treatment of DDP-induced nephrotoxicity [9]
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