Preprint Article Version 1 Preserved in Portico This version is not peer-reviewed

Oleanolic Acid Acetate Alleviates Cisplatin-Induced Nephrotoxicity Via Inhibition of the Caspase and RIPK Pathways

Bori Lee
,
Yeon-Yong Kim
,
Seungwon Jeong
ORCID logo ,
Seung Woong Lee
ORCID logo ,
Seung-Jae Lee
ORCID logo ,
Mun-Chual Rho
,
Sang-Hyun Kim
* ,
Soyoung Lee
* ORCID logo
Version 1 : Received: 14 March 2024 / Approved: 15 March 2024 / Online: 15 March 2024 (08:54:29 CET)

A peer-reviewed article of this Preprint also exists.

Lee, B.; Kim, Y.-Y.; Jeong, S.; Lee, S.W.; Lee, S.-J.; Rho, M.-C.; Kim, S.-H.; Lee, S. Oleanolic Acid Acetate Alleviates Cisplatin-Induced Nephrotoxicity via Inhibition of Apoptosis and Necroptosis In Vitro and In Vivo. Toxics 2024, 12, 301. Lee, B.; Kim, Y.-Y.; Jeong, S.; Lee, S.W.; Lee, S.-J.; Rho, M.-C.; Kim, S.-H.; Lee, S. Oleanolic Acid Acetate Alleviates Cisplatin-Induced Nephrotoxicity via Inhibition of Apoptosis and Necroptosis In Vitro and In Vivo. Toxics 2024, 12, 301.

Abstract

Cisplatin is a widely used anticancer drug for treating solid tumors, but it is associated with severe side effects, including nephrotoxicity. Various studies have suggested that the nephrotoxicity of cisplatin could be overcome; nonetheless, an effective adjuvant drug has not yet been established. Oleanolic acid acetate (OAA), a triterpenoid isolated from Vigna angularis, is commonly used to treat inflammatory and allergic diseases. This study aimed to investigate the protective effects of OAA against cisplatin-induced apoptosis and necroptosis using TCMK-1 cells and a mouse model. In cisplatin-treated TCMK-1 cells, OAA treatment significantly reduced Bax and cleaved-caspase3 expression, whereas increased Bcl-2 expression. Moreover, in cisplatin-induced kidney injury mouse model, OAA treatment alleviated weight loss in the body and major organs and also relieved cisplatin-induced nephrotoxicity symptoms. RNA sequencing analysis of kidney tissues identified lipocalin-2 as the most upregulated gene by cisplatin. Additionally, necroptosis-related genes such as receptor interacting protein kinase (RIPK) and mixed lineage kinase domain like (MLKL) were identified. In vitro study, the phosphorylation of RIPKs and MLKL was reduced by OAA pretreatment in both cisplatin-treated cells and cells boosted by co-treatment with z-VAD-FMK. In conclusion, OAA could protect the kidney from cisplatin-induced nephrotoxicity and may serve as an anticancer adjuvant.

Keywords

acute kidney injury; oleanolic acid acetate; cisplatin; necroptosis; apoptosis

Subject

Medicine and Pharmacology, Pharmacology and Toxicology

Copyright: This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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