Xinyue Zang, Peigen Wei, Chunxia Xu, Jiuyang Sun, Xiuling Yu, Deyin Wang, Z. B. Zhang, Chenxi Liu, Feng Feng, Ruoping Wang, Yang Yang
The design of multimechanistic conjugates based on 10-hydroxycamptothecin ( 10-HCPT ) offers a promising approach to reduce toxicity and enhance antitumor efficacy. We designed and synthesized a novel series of conjugates by linking melampomagnolide B ( MMB ) to 10-HCPT/SN-38 via diverse linkers. Among them, 6i1/6i2 exhibited remarkable anticolorectal cancer potency and minimal cytotoxicity toward normal THLE-2 cells. Mechanistic studies indicated that 6i1/6i2 could inhibit IκB kinase β (IKKβ), leading to the inhibition of p65 and IκBα phosphorylation, suppression of p65 nuclear translocation, and subsequent regulation of genes controlled by nuclear factor kappa-B (NF-κB). Additionally, they targeted topoisomerase I (Topo I), inducing DNA damage, reactive oxygen species (ROS) accumulation, mitochondrial membrane potential loss, and S-phase arrest. In a CT-26 xenograft model, 6i1 and 6i2 (5 mg/kg) potently suppressed tumor growth, achieving TGI rates of 89.9% and 95.4% without observable toxicity.