University of Michigan Comprehensive Cancer Center and Department of Internal Medicine, Cancer Center/3215, 1500 E. Medical Center Drive, University of Michigan, Ann Arbor, MI 48109, USA.
Mol Cancer Ther. 2011 May;10(5):902-14. doi: 10.1158/1535-7163.MCT-10-0864. Epub 2011 Mar 3.
Smac mimetics are being developed as a new class of anticancer therapies. Because the single-agent activity of Smac mimetics is very limited, rational combinations represent a viable strategy for their clinical development. The combination of Smac mimetics with TNF-related apoptosis inducing ligand (TRAIL) may be particularly attractive because of the low toxicity of TRAIL to normal cells and the synergistic antitumor activity observed for the combination. In this study, we have investigated the combination synergy between TRAIL and a potent Smac mimetic, SM-164, in vitro and in vivo and the underlying molecular mechanism of action for the synergy. Our study shows that SM-164 is highly synergistic with TRAIL in vitro in both TRAIL-sensitive and TRAIL-resistant cancer cell lines of breast, prostate, and colon cancer. Furthermore, the combination of SM-164 with TRAIL induces rapid tumor regression in vivo in a breast cancer xenograft model in which either agent is ineffective. Our data show that X-linked IAP (XIAP) and cellular IAP 1 (cIAP1), but not cIAP2, work in concert to attenuate the activity of TRAIL; SM-164 strongly enhances TRAIL activity by concurrently targeting XIAP and cIAP1. Moreover, although RIP1 plays a minimal role in the activity of TRAIL as a single agent, it is required for the synergistic interaction between TRAIL and SM-164. This study provides a strong rationale to develop the combination of SM-164 and TRAIL as a new therapeutic strategy for the treatment of human cancer.
Smac 模拟物被开发为一类新的抗癌疗法。由于 Smac 模拟物的单一活性非常有限，因此合理的组合代表了其临床开发的可行策略。Smac 模拟物与 TNF 相关凋亡诱导配体（TRAIL）的联合可能特别有吸引力，因为 TRAIL 对正常细胞的毒性较低，并且观察到联合具有协同的抗肿瘤活性。在这项研究中，我们研究了 TRAIL 和强效 Smac 模拟物 SM-164 在体外和体内的组合协同作用，以及协同作用的潜在分子作用机制。我们的研究表明，SM-164 在体外与 TRAIL 在乳腺癌、前列腺癌和结肠癌的 TRAIL 敏感和 TRAIL 耐药癌细胞系中具有高度协同作用。此外，SM-164 与 TRAIL 的组合在乳腺癌异种移植模型中体内诱导快速肿瘤消退，而单一药物均无效。我们的数据表明，X 连锁凋亡抑制蛋白（XIAP）和细胞凋亡抑制蛋白 1（cIAP1），但不是 cIAP2，协同作用以减弱 TRAIL 的活性；SM-164 通过同时靶向 XIAP 和 cIAP1 强烈增强 TRAIL 的活性。此外，尽管 RIP1 在 TRAIL 作为单一药物的活性中作用最小，但它是 TRAIL 和 SM-164 之间协同相互作用所必需的。这项研究为开发 SM-164 和 TRAIL 的联合作为人类癌症治疗的新治疗策略提供了强有力的依据。
