Identification of 2',4',6'-Trihydroxyacetophenone as Promising Cysteine Conjugate Beta-Lyase Inhibitor for Preventing Cisplatin-Induced Nephrotoxicity

Nao Sukeda; Hidetsugu Fujigaki; Tatsuya Ando; Honomi Ando; Yasuko Yamamoto; Kuniaki Saito

doi:10.1158/1535-7163.MCT-22-0564

Identification of 2',4',6'-Trihydroxyacetophenone as Promising Cysteine Conjugate Beta-Lyase Inhibitor for Preventing Cisplatin-Induced Nephrotoxicity

Mol Cancer Ther. 2023 Jun 7:OF1-OF9. doi: 10.1158/1535-7163.MCT-22-0564. Online ahead of print.

Authors

Nao Sukeda¹, Hidetsugu Fujigaki¹, Tatsuya Ando², Honomi Ando¹, Yasuko Yamamoto¹, Kuniaki Saito¹

Affiliations

¹ Department of Advanced Diagnostic System Development, Fujita Health University Graduate School of Health Sciences, Aichi, Japan.
² Department of Joint Research Laboratory of Clinical Medicine, Fujita Health University School of Medicine, Aichi, Japan.

PMID: 37294883
DOI: 10.1158/1535-7163.MCT-22-0564

Abstract

Cisplatin is a chemotherapeutic agent used to treat many types of malignant tumors. However, irrespective of its potent anticancer properties and efficacy, nephrotoxicity is the dose-limiting factor of cisplatin treatment. Cisplatin infiltrates renal tubular cells in the kidneys and is metabolized by cysteine conjugate-beta lyase 1 (CCBL1) to form highly reactive thiol-cisplatin; this may mediate cisplatin's nephrotoxicity. Therefore, CCBL1 inhibition may prevent cisplatin-induced nephrotoxicity. Using a high-throughput screening assay, we identified 2',4',6'-trihydroxyacetophenone (THA) as an inhibitor of CCBL1. THA inhibited human CCBL1 β-elimination activity in a concentration-dependent manner. We further investigated the preventive effect of THA on cisplatin-induced nephrotoxicity. THA attenuated the effect of cisplatin on the viability of confluent renal tubular cells (LLC-PK1 cells) but had no effect on cisplatin-induced reduction of proliferation in the tumor cell lines (LLC and MDA-MB-231). THA pretreatment significantly attenuated cisplatin-induced increases in blood urea nitrogen, creatinine, cell damage score, and apoptosis of renal tubular cells in mice in a dose-dependent manner. Furthermore, THA pretreatment attenuated cisplatin-induced nephrotoxicity without compromising its antitumor activities in mice bearing subcutaneous syngeneic LLC tumors. THA could help prevent cisplatin-induced nephrotoxicity and may provide a new strategy for cisplatin-inclusive cancer treatments.