Discovery of preventive drugs for cisplatin‐induced acute kidney injury using big data analysis

Abstract

Cisplatin is effective against many types of carcinoma. However, a high rate of renal damage is a clinical problem. Thus, there is a need to establish a method to prevent it. Although various compounds have been reported to be effective against cisplatin-induced renal injury, there are no examples of their clinical application. Therefore, we attempted to search for prophylactic agents with a high potential for clinical application. We used Cascade Eye to identify genes that are altered during cisplatin-induced renal injury, Library of Integrated Network-based Cellular Signatures (LINCS) to identify drugs that inhibit changes in gene expression, and a large database of spontaneous adverse drug reaction reports to identify drugs that could prevent cisplatin-induced kidney injury in clinical practice. In total, 10 candidate drugs were identified. Using the US Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS), we identified drugs that reduce cisplatin-induced kidney injury.Fenofibrate was selected as a candidate drug to prevent cisplatin-induced kidney injury based on the FAERS analysis. A model was used to evaluate the efficacy of fenofibrate against cisplatin-induced renal injury. Studies using HK2 cells and mouse models showed that fenofibrate significantly inhibited cisplatin-induced renal injury but did not inhibit the antitumor effect of cisplatin. Fenofibrate is a candidate prophylactic drug with high clinical applicability for cisplatin-induced renal injury. Analysis of data from multiple big databases will improve the search for novel prophylactic drugs with high clinical applicability. For the practical application of these findings, evaluation in prospective controlled trials is necessary.

Valproic acid treatment attenuates cisplatin‐induced kidney injury by suppressing proximal tubular cell damage

“…The relative humidity and temperature of the breeding room were 50% ± 10%, and 26°C ± 1°C, respectively, following a 12‐h light–dark cycle (on at 8:00 h, off at 20:00 h). To establish a mouse model of cisplatin‐induced renal injury, we used C57BL/6N male mice following established protocols described previously 18,19 …”

“…To establish a mouse model of cisplatin-induced renal injury, we used C57BL/6N male mice following established protocols described previously. 18,19 Mice were randomly allocated to six groups (n = 5-8 mice/group): group 1, vehicle-injected; group 2, VPAtreated; group 3, cisplatin-injected; and groups 4-6, cisplatin-injected with add-on VPA at 10, 30, and 100 mg/kg, respectively. Mice were intraperitoneally injected with cisplatin (groups 3-6, 15 mg/kg) or vehicle (groups 1 and 2, saline) once.…”