Department of Dermatology, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China.
Core Research Laboratory, The Second Affiliated Hospital, School of Medicine, Xi'an Jiaotong University, Xi'an, China.
J Invest Dermatol. 2023 Feb;143(2):242-253.e6. doi: 10.1016/j.jid.2022.08.039. Epub 2022 Sep 3.
The mimetic of SMAC induced cell death in cancers by depleting the inhibitor of apoptosis proteins. Recent studies showed that Fn14 is overexpressed in the cells of squamous cell carcinoma (SCC), providing a promising candidate target for selective antitumor therapy. In this study, we conjugated a small-molecule SMAC mimetic MV1 to the ligand of Fn14, TWEAK. Our results showed that TWEAK‒MV1 conjugate retained adequate binding specificity to Fn14-positive SCC cells in vitro and accumulated selectively in tumor tissue of cutaneous SCC xenografts mice after intraperitoneal administration. This conjugation compound exhibited remarkable effectiveness in suppressing tumor growth and extending overall survival without causing significant side effects in SCC xenograft mice. Moreover, TWEAK‒MV1 conjugate greatly enhanced both apoptotic and necroptotic cell death both in vitro and in vivo, accompanied by a cellular inhibitor of apoptosis proteins degradation as well as activation of receptor-interacting protein kinase. Taken together, our preclinical data suggested that the designed conjugation compound of TWEAK and MV1 might provide a potential therapeutic strategy for cutaneous SCC with improved antitumor efficacy and negligible toxicity.
SMAC 模拟物通过耗尽凋亡抑制蛋白诱导癌症细胞死亡。最近的研究表明，Fn14 在鳞状细胞癌 (SCC) 细胞中过表达，为选择性抗肿瘤治疗提供了一个有前途的候选靶点。在这项研究中，我们将小分子 SMAC 模拟物 MV1 与 Fn14 的配体 TWEAK 偶联。我们的结果表明，TWEAK-MV1 缀合物在体外保留了对 Fn14 阳性 SCC 细胞的足够结合特异性，并在腹腔给药后在皮肤 SCC 异种移植小鼠的肿瘤组织中选择性积累。该缀合物在 SCC 异种移植小鼠中表现出显著的抑制肿瘤生长和延长总生存期的效果，而没有引起明显的副作用。此外，TWEAK-MV1 缀合物在体外和体内均显著增强了凋亡和坏死性细胞死亡，伴随着细胞凋亡抑制蛋白的降解以及受体相互作用蛋白激酶的激活。总之，我们的临床前数据表明，TWEAK 和 MV1 的设计缀合物可能为皮肤 SCC 提供一种潜在的治疗策略，具有改善的抗肿瘤疗效和可忽略的毒性。
