Tong Yin, You Liangshun, Liu Hui, Li Lu, Meng Haitao, Qian Qijun, Qian Wenbin
Institute of Hematology, the First Affiliated Hospital, College of Medicine, Zhejiang University, P.R. China.
Oncotarget. 2013 Jun;4(6):860-74. doi: 10.18632/oncotarget.1018.
An attractive strategy among adenovirus-based oncolytic systems is to design adenoviral vectors to express pro-apoptotic genes, in which this gene-virotherapy approach significantly enhances tumor cell death by activating apoptotic pathways. However, the existence of cancer cells with apoptotic defects is one of the major obstacles in gene-virotherapy. Here, we investigated whether a strategy that combines the oncolytic effects of an adenoviral vector with simultaneous expression of Beclin-1, an autophagy gene, offers a therapeutic advantage for leukemia. A Beclin-1 cDNA was cloned in an oncolytic adenovirus with chimeric Ad5/11 fiber (SG511-BECN). SG511-BECN treatment induced significant autophagic cell death, and resulted in enhanced cell killing in a variety of leukemic cell lines and primary leukemic blasts. SG511-BECN effects were seen in chronic myeloid leukemia and acute myeloid leukemia with resistance to imatinib or chemotherapy, but exhibited much less cytotoxicity on normal cells. The SG511-BECN-induced autophagic cell death could be partially reversed by RNA interference knockdown of UVRAG, ATG5, and ATG7. We also showed that SG511-BECN strongly inhibited the growth of leukemic progenitors in vitro. In murine leukemia models, SG511-BECN prolonged the survival and decreased the xenograft tumor size by inducing autophagic cell death. Our results suggest that infection of leukemia cells with an oncolytic adenovirus overexpressing Beclin-1 can induce significant autophagic cell death and provide a new strategy for the elimination of leukemic cells via a unique mechanism of action distinct from apoptosis.
在基于腺病毒的溶瘤系统中，一种引人注目的策略是设计腺病毒载体来表达促凋亡基因，这种基因病毒疗法通过激活凋亡途径显著增强肿瘤细胞死亡。然而，存在凋亡缺陷的癌细胞是基因病毒疗法的主要障碍之一。在这里，我们研究了一种将腺病毒载体的溶瘤作用与自噬基因Beclin-1的同时表达相结合的策略是否对白血病具有治疗优势。将Beclin-1 cDNA克隆到具有嵌合Ad5/11纤维的溶瘤腺病毒中（SG511-BECN）。SG511-BECN治疗诱导了显著的自噬性细胞死亡，并导致在多种白血病细胞系和原代白血病细胞中增强细胞杀伤作用。在对伊马替尼或化疗耐药的慢性髓性白血病和急性髓性白血病中观察到SG511-BECN的作用，但对正常细胞的细胞毒性要小得多。通过RNA干扰敲低UVRAG、ATG5和ATG7可部分逆转SG511-BECN诱导的自噬性细胞死亡。我们还表明，SG511-BECN在体外强烈抑制白血病祖细胞的生长。在小鼠白血病模型中，SG511-BECN通过诱导自噬性细胞死亡延长了生存期并减小了异种移植肿瘤的大小。我们的数据表明，用过量表达Beclin-1的溶瘤腺病毒感染白血病细胞可诱导显著的自噬性细胞死亡，并通过一种不同于凋亡的独特作用机制为消除白血病细胞提供一种新策略。
