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

Author:

Sukeda Nao1ORCID,Fujigaki Hidetsugu1ORCID,Ando Tatsuya2ORCID,Ando Honomi1ORCID,Yamamoto Yasuko1ORCID,Saito Kuniaki1ORCID

Affiliation:

1. 1Department of Advanced Diagnostic System Development, Fujita Health University Graduate School of Health Sciences, Aichi, Japan.

2. 2Department of Joint Research Laboratory of Clinical Medicine, Fujita Health University School of Medicine, Aichi, Japan.

Abstract

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.

Funder

Japan Society for the Promotion of Science

Publisher

American Association for Cancer Research (AACR)

Subject

Cancer Research,Oncology

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