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Full Length Article | Open Access

Novel oral compound Z526 mitigates cancer-associated cachexia via intervening NF-κB signaling and oxidative stress

Xiaofan Gua, Shanshan Lua, Shuang Xub, Yiwei Lia, Meng Fana, Guangyu Linb, Yiyuan Liua, Yun Zhaoa, Weili Zhaob, Xuan Liuc, Xiaochun Dongb( ), Xiongwen Zhanga( )
Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, School of Chemistry and Molecular Engineering, East China Normal University, Shanghai 200062, China
Department of Medicinal Chemistry, School of Pharmacy, Fudan University, Shanghai 201210, China
Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China

Peer review under the responsibility of the Genes & Diseases Editorial Office, in alliance with the Association of Chinese Americans in Cancer Research (ACACR, Baltimore, MD, USA).

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Abstract

Cancer-associated cachexia (CAC) is a severe metabolic disorder syndrome mainly characterized by muscle and fat loss, which accounts for one-third of cancer-related deaths. No effective therapeutic approach that could fully reverse CAC is available. NF-κB signaling and oxidative stress play vital roles in both muscle atrophy and fat loss in CAC. Here, we showed that our developed oral compound Z526 exhibited potent anti-CAC efficacy by inhibiting NF-κB signaling and ameliorating oxidative stress. In vitro, Z526 alleviated C2C12 myotube atrophy and 3T3-L1 adipocyte lipolysis induced by conditioned mediums of multiple cachectic tumor cells or pro-cachectic inflammatory cytokines. In vivo, Z526 attenuated the cachectic symptoms of C26 or LLC tumor-bearing mice. Z526 treatment reduced weight loss without impacting tumor growth and improved muscle atrophy, fat loss, and impaired grip force. Besides, serum TNF-α and IL-6 levels were reduced after Z526 treatment in C26 tumor-bearing mice. Of note, Z526 significantly prolonged the survival of LLC tumor-bearing mice. Activated NF-κB signaling and oxidative stress in cachectic muscle and fat tissues were reversed by Z526. Furthermore, Z526 exhibited a promising preclinical safety profile. Thus, oral Z526, which exhibited potent anti-CAC activities in vitro and in vivo, multiple interventions in diverse pathogenic mechanisms (NF-κB signaling and oxidative stress), and a favorable preclinical safety profile, holds the promise to be developed into a novel and beneficial therapeutic option for CAC.

Keywords

Cancer-associated cachexiaFat lipolysisMuscle atrophyNF-κB signalingOxidative stressZ526

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Genes & Diseases
Volume 12 Issue 2,
March 2025
Article number: 101292
DOI: 10.1016/j.gendis.2024.101292
Cite this article:
Gu X, Lu S, Xu S, et al. Novel oral compound Z526 mitigates cancer-associated cachexia via intervening NF-κB signaling and oxidative stress. Genes & Diseases, 2025, 12(2): 101292. https://doi.org/10.1016/j.gendis.2024.101292

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Received: 02 August 2023
Revised: 02 February 2024
Accepted: 07 March 2024
Published: 08 April 2024
© 2024 The Authors.

This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
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