Selective Antagonism of Bcl-xL Potentiates M1 Oncolysis by Enhancing Mitochondrial Apoptosis
Selective Antagonism of Bcl-xL Potentiates M1 Oncolysis by Enhancing Mitochondrial Apoptosis
复制标题
Bcl-xL 的选择性拮抗作用通过增强线粒体凋亡来增强 M1 溶瘤作用。
DOI：
10.1089/hum.2017.055
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发表时间：
2018-08-01
影响因子：
4.2
通讯作者：
Zhang, Haipeng
中科院分区：
文献类型：
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作者：
Tan, Yaqian;Lin, Yuan;Zhang, Haipeng
溶瘤病毒治疗是一种新颖而有趣的肿瘤治疗策略。然而，溶瘤病毒作为单一药物的临床潜力有限。M1病毒是一种有前途的溶瘤病毒，已在临床前研究中进行了测试。在这项研究中，我们研究了M1病毒和Bcl-2家族抑制剂联合使用的效果。包括10种Bcl-2家族抑制剂的化合物筛选表明，pan-Bcl-2抑制剂在非常低的剂量下选择性地增强了M1病毒在癌细胞中的溶瘤作用。Pan-Bcl-2抑制剂与M1病毒协同增强抗肿瘤作用的机制主要是由于Bcl-xL的抑制，其与M1诱导的巴克的上调协同作用以触发细胞凋亡。在异种移植小鼠模型和患者来源的肿瘤组织中，M1和pan-Bcl-2抑制剂的组合显著抑制肿瘤生长并延长生存期，表明该策略的潜在治疗价值。这些发现提供了对Bcl-xL抑制和溶瘤病毒M1作为组合抗癌治疗方式之间的协同作用的见解。
Oncolytic virotherapy is a novel and intriguing treatment strategy for cancer therapy. However, the clinical potential of oncolytic virus as single agent is limited. M1 virus is a promising oncolytic virus that has been tested in preclinical studies. In this study, we investigated the effect of the combination use of M1 virus and Bcl-2 family inhibitors. A chemical compounds screening including ten Bcl-2 family inhibitors demonstrated that pan-Bcl-2 inhibitors selectively augmented M1 virus oncolysis in cancer cells at very low doses. The mechanism of the enhanced antitumor effect of pan-Bcl-2 inhibitors with M1 virus is mainly due to the inhibition of Bcl-xL, which synergizes with M1-induced upregulation of Bak to trigger apoptosis. In xenograft mouse models and patient-derived tumor tissues, the combination of M1 and pan-Bcl-2 inhibitors significantly inhibited tumor growth and prolonged survival, suggesting the potential therapeutic value of this strategy. These findings offer insights into the synergy between Bcl-xL inhibition and oncolytic virus M1 as a combination anticancer treatment modality.