Solange Gauthier Karsh Molecular Genetics Laboratory, Apoptosis Research Centre, Children's Hospital of Eastern Ontario Research Institute, Ottawa, Ontario, Canada.
Alberta Children's Hospital Research Institute, Department of Microbiology, Immunology and Infectious Disease, University of Calgary, Calgary, Alberta, Canada.
Nat Biotechnol. 2014 Feb;32(2):182-90. doi: 10.1038/nbt.2806. Epub 2014 Jan 26.
Smac mimetic compounds (SMC), a class of drugs that sensitize cells to apoptosis by counteracting the activity of inhibitor of apoptosis (IAP) proteins, have proven safe in phase 1 clinical trials in cancer patients. However, because SMCs act by enabling transduction of pro-apoptotic signals, SMC monotherapy may be efficacious only in the subset of patients whose tumors produce large quantities of death-inducing proteins such as inflammatory cytokines. Therefore, we reasoned that SMCs would synergize with agents that stimulate a potent yet safe "cytokine storm." Here we show that oncolytic viruses and adjuvants such as poly(I:C) and CpG induce bystander death of cancer cells treated with SMCs that is mediated by interferon beta (IFN-β), tumor necrosis factor alpha (TNF-α) and/or TNF-related apoptosis-inducing ligand (TRAIL). This combinatorial treatment resulted in tumor regression and extended survival in two mouse models of cancer. As these and other adjuvants have been proven safe in clinical trials, it may be worthwhile to explore their clinical efficacy in combination with SMCs.
Smac 模拟物（SMC）是一类药物，通过拮抗凋亡抑制蛋白（IAP）的活性使细胞对细胞凋亡敏感，在癌症患者的 1 期临床试验中已被证明安全。然而，由于 SMC 通过使促凋亡信号转导成为可能，因此 SMC 单药治疗可能仅对那些肿瘤产生大量诱导死亡蛋白（如炎症细胞因子）的患者亚组有效。因此，我们推断 SMC 与刺激有效且安全的“细胞因子风暴”的药物联合使用会产生协同作用。在这里，我们表明溶瘤病毒和佐剂（如聚肌苷酸和 CpG）可诱导经 SMC 处理的癌细胞发生旁观者死亡，这是由干扰素β（IFN-β）、肿瘤坏死因子-α（TNF-α）和/或 TNF 相关凋亡诱导配体（TRAIL）介导的。这种联合治疗导致两种癌症小鼠模型中的肿瘤消退和生存时间延长。由于这些佐剂和其他佐剂已在临床试验中被证明安全，因此探索它们与 SMC 联合使用的临床疗效可能是值得的。
