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.

FIGURE 1

Effect of fenofibrate on cisplatin‐induced nephrotoxicity. (a, b) The mRNA expression levels of kidney injury markers Kim‐1 (a) and Lcn‐2 (b) in the kidneys of mice in each group. (c) Representative hematoxylin and eosin staining (HE) of the kidney section of the control mice, cisplatin‐injected mice with vehicle or fenofibrate. The scale bar indicates 100 μm. (d) Quantitative analysis of renal damage scores. Values are expressed as mean ± SEM. Cis, cisplatin; Feno, fenofibrate. ^† p < 0.05 versus vehicle mice, *p < 0.01 versus cisplatin mice, n = 4–9 in each group

FIGURE 2

Effect of fenofibrate on inflammatory cytokine expression in the kidneys. The mRNA expression levels of inflammatory cytokines IL‐1β (a), IL‐6 (b), and TNF‐α (c) in the kidneys of mice in each group. Values are expressed as mean ± SEM. Cis, cisplatin; Feno, fenofibrate. ^† p < 0.05 versus vehicle mice, *p < 0.01 versus cisplatin mice, n = 4–9 in each group

FIGURE 3

Effect of fibrates on cisplatin cytotoxicity using HK2 cells. Cell viability after 24 h of incubation in medium with or without 50 μM cisplatin was calculated as 100% for the vehicle group. (a, b) Fenofibrate (1, 10, 100 μM) a or bezafibrate (1, 10, 100 μM) b was administered simultaneously with cisplatin. (c) The 2 μM of GW6471, a PPARα inhibitor, was used. Values are expressed as mean ± SEM. Cis, cisplatin; Beza, bezafibrate; Feno, fenofibrate; GW, GW6471. ^† p < 0.05 versus vehicle, *p < 0.01 versus cisplatin, n = 8 in each group

FIGURE 4

Effect of fibrates on the anticancer effect of cisplatin on tumor cells, LLC (a), Colon‐26 (b). Cell viability after 24 h of incubation in medium with or without 50 μM cisplatin was calculated as 100% for the vehicle group. Fenofibrate (100 μM) was administered simultaneously with cisplatin. Values are expressed as mean ± SEM. Cis, cisplatin; Feno, fenofibrate. ^† p < 0.05 versus vehicle. N.S. indicates not significant. n = 16 in each group