Shekhar Tanmay M, Miles Mark A, Gupte Ankita, Taylor Scott, Tascone Brianna, Walkley Carl R, Hawkins Christine J
Department of Biochemistry and Genetics, La Trobe Institute for Molecular Science, La Trobe University, Bundoora, Victoria, Australia.
St. Vincent's Institute of Medical Research, Fitzroy, Australia; Department of Medicine, St. Vincent's Hospital, University of Melbourne, Fitzroy, Australia.
Oncotarget. 2016 Jun 7;7(23):33866-86. doi: 10.18632/oncotarget.8980.
Outcomes for patients diagnosed with the bone cancer osteosarcoma have not improved significantly in the last four decades. Only around 60% of patients and about a quarter of those with metastatic disease survive for more than five years. Although DNA-damaging chemotherapy drugs can be effective, they can provoke serious or fatal adverse effects including cardiotoxicity and therapy-related cancers. Better and safer treatments are therefore needed. We investigated the anti-osteosarcoma activity of IAP antagonists (also known as Smac mimetics) using cells from primary and metastatic osteosarcomas that arose spontaneously in mice engineered to lack p53 and Rb expression in osteoblast-derived cells. The IAP antagonists SM-164, GDC-0152 and LCL161, which efficiently target XIAP and cIAPs, sensitized cells from most osteosarcomas to killing by low levels of TNFα but not TRAIL. RIPK1 expression levels and activity correlated with sensitivity. RIPK3 levels varied considerably between tumors and RIPK3 was not required for IAP antagonism to sensitize osteosarcoma cells to TNFα. IAP antagonists, including SM-164, lacked mutagenic activity. These data suggest that drugs targeting XIAP and cIAP1/2 may be effective for osteosarcoma patients whose tumors express abundant RIPK1 and contain high levels of TNFα, and would be unlikely to provoke therapy-induced cancers in osteosarcoma survivors.
在过去的四十年里，被诊断患有骨肉瘤这种骨癌的患者的治疗结果并没有显著改善。只有大约60%的患者以及四分之一的转移性疾病患者能存活超过五年。尽管具有DNA损伤作用的化疗药物可能有效，但它们会引发严重或致命的不良反应，包括心脏毒性和与治疗相关的癌症。因此，需要更好、更安全的治疗方法。我们使用在成骨细胞衍生细胞中缺乏p53和Rb表达的工程小鼠自发产生的原发性和转移性骨肉瘤细胞，研究了IAP拮抗剂（也称为Smac模拟物）的抗骨肉瘤活性。IAP拮抗剂SM - 164、GDC - 0152和LCL161能有效靶向XIAP和cIAPs，使大多数骨肉瘤细胞对低水平的TNFα诱导的杀伤敏感，但对TRAIL不敏感。RIPK1的表达水平和活性与敏感性相关。肿瘤之间RIPK3水平差异很大，IAP拮抗剂使骨肉瘤细胞对TNFα敏感并不需要RIPK3。包括SM - 164在内的IAP拮抗剂缺乏诱变活性。这些数据表明，靶向XIAP和cIAP1/2的药物可能对肿瘤表达大量RIPK1且含有高水平TNFα的骨肉瘤患者有效，并且不太可能在骨肉瘤幸存者中引发治疗诱导的癌症。
