title: Potent antitumor activity of oncolytic adenovirus expressing Beclin-1 via induction of autophagic cell death in leukemia.
abstract: 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.
authors.affiliation: Institute of Hematology, the First Affiliated Hospital, College of Medicine, Zhejiang University, P.R. China.
authors.forename: Yin
authors.initials: Y
authors.lastname: Tong
authors.forename: Liangshun
authors.initials: L
authors.lastname: You
authors.forename: Hui
authors.initials: H
authors.lastname: Liu
authors.forename: Lu
authors.initials: L
authors.lastname: Li
authors.forename: Haitao
authors.initials: H
authors.lastname: Meng
authors.forename: Qijun
authors.initials: Q
authors.lastname: Qian
authors.forename: Wenbin
authors.initials: W
authors.lastname: Qian
mesh_terms: D000256:Adenoviridae / Q000235:genetics / Q000502:physiology; D000328:Adult; D000368:Aged; D000818:Animals; D017209:Apoptosis / Q000502:physiology; D051017:Apoptosis Regulatory Proteins / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D001343:Autophagy / Q000235:genetics; D000071186:Beclin-1; D045744:Cell Line, Tumor; D005260:Female; D006801:Humans; D020014:K562 Cells; D007938:Leukemia / Q000235:genetics / Q000473:pathology / Q000628:therapy* / Q000821:virology*; D008297:Male; D008565:Membrane Proteins / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008875:Middle Aged; D050130:Oncolytic Virotherapy / Q000379:methods*; D050504:Oncolytic Viruses / Q000235:genetics / Q000502:physiology*; D011897:Random Allocation; D014162:Transfection; D023041:Xenograft Model Antitumor Assays; D055815:Young Adult
chemical_list: D051017:Apoptosis Regulatory Proteins; C491997:BECN1 protein, human; D000071186:Beclin-1; D008565:Membrane Proteins