Gu Xiaofan, Lu Shanshan, Xu Shuang, Li Yiwei, Fan Meng, Lin Guangyu, Liu Yiyuan, Zhao Yun, Zhao Weili, Liu Xuan, Dong Xiaochun, Zhang Xiongwen
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.
Genes Dis. 2024 Apr 8;12(2):101292. doi: 10.1016/j.gendis.2024.101292. eCollection 2025 Mar.
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. , Z526 alleviated C2C12 myotube atrophy and 3T3-L1 adipocyte lipolysis induced by conditioned mediums of multiple cachectic tumor cells or pro-cachectic inflammatory cytokines. , 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 and , 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.
癌症恶病质（CAC）是一种严重的代谢紊乱综合征，主要特征为肌肉和脂肪流失，其导致的死亡占癌症相关死亡人数的三分之一。目前尚无能够完全逆转CAC的有效治疗方法。NF-κB信号通路和氧化应激在CAC的肌肉萎缩和脂肪流失过程中均起着关键作用。在此，我们表明，我们研发的口服化合物Z526通过抑制NF-κB信号通路和减轻氧化应激，展现出强大的抗CAC疗效。Z526减轻了多种恶病质肿瘤细胞条件培养基或促恶病质炎性细胞因子诱导的C2C12肌管萎缩和3T3-L1脂肪细胞脂解。Z526减轻了C26或LLC荷瘤小鼠的恶病质症状。Z526治疗减少了体重减轻，同时不影响肿瘤生长，并改善了肌肉萎缩、脂肪流失和握力受损的情况。此外，在C26荷瘤小鼠中，Z526治疗后血清TNF-α和IL-6水平降低。值得注意的是，Z526显著延长了LLC荷瘤小鼠的生存期。Z526逆转了恶病质肌肉和脂肪组织中激活的NF-κB信号通路和氧化应激。此外，Z526展现出良好的临床前安全性。因此，口服Z526具有强大的抗CAC活性，对多种致病机制（NF-κB信号通路和氧化应激）具有多重干预作用，且临床前安全性良好，有望开发成为一种针对CAC的新型有益治疗选择。
