Novel oral compound Z526 mitigates cancer-associated cachexia via intervening NF-κB signaling and oxidative stress
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 ro...
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| Format: | Article |
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KeAi Communications Co., Ltd.
2025-03-01
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| Series: | Genes and Diseases |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2352304224000898 |
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| author | Xiaofan Gu Shanshan Lu Shuang Xu Yiwei Li Meng Fan Guangyu Lin Yiyuan Liu Yun Zhao Weili Zhao Xuan Liu Xiaochun Dong Xiongwen Zhang |
| author_facet | Xiaofan Gu Shanshan Lu Shuang Xu Yiwei Li Meng Fan Guangyu Lin Yiyuan Liu Yun Zhao Weili Zhao Xuan Liu Xiaochun Dong Xiongwen Zhang |
| author_sort | Xiaofan Gu |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-d9666a9612cd48c2a813ee2a4656047a |
| institution | DOAJ |
| issn | 2352-3042 |
| language | English |
| publishDate | 2025-03-01 |
| publisher | KeAi Communications Co., Ltd. |
| record_format | Article |
| series | Genes and Diseases |
| spelling | doaj-art-d9666a9612cd48c2a813ee2a4656047a2025-08-20T02:39:11ZengKeAi Communications Co., Ltd.Genes and Diseases2352-30422025-03-0112210129210.1016/j.gendis.2024.101292Novel oral compound Z526 mitigates cancer-associated cachexia via intervening NF-κB signaling and oxidative stressXiaofan Gu0Shanshan Lu1Shuang Xu2Yiwei Li3Meng Fan4Guangyu Lin5Yiyuan Liu6Yun Zhao7Weili Zhao8Xuan Liu9Xiaochun Dong10Xiongwen Zhang11Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, School of Chemistry and Molecular Engineering, East China Normal University, Shanghai 200062, ChinaShanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, School of Chemistry and Molecular Engineering, East China Normal University, Shanghai 200062, ChinaDepartment of Medicinal Chemistry, School of Pharmacy, Fudan University, Shanghai 201210, ChinaShanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, School of Chemistry and Molecular Engineering, East China Normal University, Shanghai 200062, ChinaShanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, School of Chemistry and Molecular Engineering, East China Normal University, Shanghai 200062, ChinaDepartment of Medicinal Chemistry, School of Pharmacy, Fudan University, Shanghai 201210, ChinaShanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, School of Chemistry and Molecular Engineering, East China Normal University, Shanghai 200062, ChinaShanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, School of Chemistry and Molecular Engineering, East China Normal University, Shanghai 200062, ChinaDepartment of Medicinal Chemistry, School of Pharmacy, Fudan University, Shanghai 201210, ChinaInstitute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, ChinaDepartment of Medicinal Chemistry, School of Pharmacy, Fudan University, Shanghai 201210, China; Corresponding author.Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, School of Chemistry and Molecular Engineering, East China Normal University, Shanghai 200062, China; Corresponding author.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.http://www.sciencedirect.com/science/article/pii/S2352304224000898Cancer-associated cachexiaFat lipolysisMuscle atrophyNF-κB signalingOxidative stressZ526 |
| spellingShingle | Xiaofan Gu Shanshan Lu Shuang Xu Yiwei Li Meng Fan Guangyu Lin Yiyuan Liu Yun Zhao Weili Zhao Xuan Liu Xiaochun Dong Xiongwen Zhang Novel oral compound Z526 mitigates cancer-associated cachexia via intervening NF-κB signaling and oxidative stress Genes and Diseases Cancer-associated cachexia Fat lipolysis Muscle atrophy NF-κB signaling Oxidative stress Z526 |
| title | Novel oral compound Z526 mitigates cancer-associated cachexia via intervening NF-κB signaling and oxidative stress |
| title_full | Novel oral compound Z526 mitigates cancer-associated cachexia via intervening NF-κB signaling and oxidative stress |
| title_fullStr | Novel oral compound Z526 mitigates cancer-associated cachexia via intervening NF-κB signaling and oxidative stress |
| title_full_unstemmed | Novel oral compound Z526 mitigates cancer-associated cachexia via intervening NF-κB signaling and oxidative stress |
| title_short | Novel oral compound Z526 mitigates cancer-associated cachexia via intervening NF-κB signaling and oxidative stress |
| title_sort | novel oral compound z526 mitigates cancer associated cachexia via intervening nf κb signaling and oxidative stress |
| topic | Cancer-associated cachexia Fat lipolysis Muscle atrophy NF-κB signaling Oxidative stress Z526 |
| url | http://www.sciencedirect.com/science/article/pii/S2352304224000898 |
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