Lee, Dahae Yamabe, Noriko Lee, Heesu Lee, Hye Lim Kim, Dong-Wook Lee, Jae Wook Kang, Ki Sung 2024-01-19T14:00:27Z 2024-01-19T14:00:27Z 2021-10-21 2021-09-15 0960-894X https://pubs.kist.re.kr/handle/201004/116469 Acute kidney injury (AKI) is a common clinical problem that is associated with high mortality due to multiple complex mechanisms. Cisplatin is the most important and highly effective chemotherapeutic agent used for the treatment of various solid tumors; however, it is associated with dose-dependent adverse effects, particularly in the kidney where it can cause severe nephrotoxicity. The pathophysiological basis of cisplatin-induced nephrotoxicity has been investigated over the last few decades, and the key pathological occurrences in cisplatin nephrotoxicity include renal tubular cell injury and death. Necrostatin-1 (Nec-1) has been confirmed to act as a specific and potent small-molecule inhibitor of necroptosis. However, the effects of three structurally distinct necrostatins on cisplatin-induced nephrotoxicity remain ambiguous. The aim of this study was to determine if three types of necrostatins (Nec-1, Nec-3-A, and/or Nec-3-B) can exert protective effects in regard to the AKI induced by cisplatin. Our results indicated that necrostatins can prevent cisplatin induced nephrotoxicity via modulating apoptotic pathways through the suppression of cleaved caspase-3 and also by influencing the function of mitogen-activated protein kinase pathway members, including extracellular signal-regulated kinases, c-Jun N-terminal kinases, and p38, in the renal tubular epithelial cell line LLC-PK1. These findings suggest that necrostatins exert beneficial anti-apoptotic effects in the context of AKI induced by cisplatin. English Pergamon Press Ltd. ACUTE KIDNEY INJURY OXIDATIVE STRESS N-ACETYLCYSTEINE CANCER-THERAPY KINASE ACTIVATION IDENTIFICATION INVOLVEMENT MECHANISMS TOXICITY Necrostatins regulate apoptosis, necroptosis, and inflammation in cisplatin-induced nephrotoxicity in LLC-PK1 cells Article 10.1016/j.bmcl.2021.128256 1 Bioorganic & Medicinal Chemistry Letters, v.48 Bioorganic & Medicinal Chemistry Letters 48 scie scopus 000684377000015 2-s2.0-85109939152 Chemistry, Medicinal Chemistry, Organic Pharmacology & Pharmacy Chemistry Article ACUTE KIDNEY INJURY OXIDATIVE STRESS N-ACETYLCYSTEINE CANCER-THERAPY KINASE ACTIVATION IDENTIFICATION INVOLVEMENT MECHANISMS TOXICITY Necrostatins Cisplatin Acute kidney injury Apoptosis Caspase Mitogen-activated protein kinases