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 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.