Development of Therapeutic Strategies for Anticancer Drug-Induced Acute Nephrotoxicity on Novel Cell Death Pathways

2021 Fiscal Year Final Research Report

• Project/Area Number: 20K17285
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 53040:Nephrology-related
• Research Institution: The University of Tokushima
• Principal Investigator: HAMANO Hirofumi 徳島大学, 病院, 特任助教 (10847289)
• Project Period (FY): 2020-04-01 – 2022-03-31
• Keywords: フェロトーシス / シスプラチン / 鉄

Outline of Final Research Achievements

The mechanism of cisplatin-induced nephrotoxicity (CIN) has long been investigated in order to develop preventive/therapeutic drugs. Ferroptosis is a newly identified form of non-apoptotic regulated cell death induced by iron-mediated lipid peroxidation and is involved in the pathophysiology of various diseases. In this study, we examined the role of ferroptosis in CIN. We evaluated the role of ferroptosis in CIN by in vivo experiments in a mouse model. Treatment with cisplatin augmented renal ferrous iron and hydroxyl radical levels with co-localization. Mice administered cisplatin demonstrated kidney injury, with renal dysfunction and the ferroptosis markers, COX2 and 4-hydroxynonenal (4-HNE); these changes were ameliorated by Ferrostatin-1 (Fer-1), an inhibitor of ferroptosis. Ferroptosis is involved in the pathogenesis of CIN and might be used as a new preventive target for CIN.

Free Research Field

薬理

Academic Significance and Societal Importance of the Research Achievements

フェロトーシスがシスプラチン誘発腎毒性（CIN）の病態生理に関与していることを明らかにした。シスプラチン投与により、腎臓の鉄量とトランスフェリンレセプターの発現、第一鉄量が増加し、フェロトーシス阻害剤でCINが抑制された。このように、フェロトーシスは、総鉄および第一鉄の含有量を増加させることにより、CIN の病態生理に関与している可能性があり、その阻害は、CINの予防のための治療ターゲットとなりうることが示唆された。フェロトーシスが CIN の予防標的であることを確認するためには、さらなる調査が必要である。