title: Synergistic antitumor activity of triple-regulated oncolytic adenovirus with VSTM1 and daunorubicin in leukemic cells.
abstract: V-set and transmembrane domain-containing 1 (VSTM1), which is downregulated in bone marrow cells from leukemia patients, may provide a diagnostic and treatment target. Here, a triple-regulated oncolytic adenovirus was constructed to carry a VSTM1 gene expression cassette, SG611-VSTM1, and contained the E1a gene with a 24-nucleotide deletion within the CR2 region under control of the human telomerase reverse transcriptase promoter, E1b gene directed by the hypoxia response element, and VSTM1 gene controlled by the cytomegalovirus promoter. Real-time quantitative PCR and Western blot analyses showed that SG611-VSTM1 expressed VSTM1 highly efficiently in the human leukemic cell line K562 compared with SG611. In Cell Counting Kit-8 and flow cytometric assays, SG611-VSTM1 exhibited more potent anti-proliferative and pro-apoptotic effects in leukemic cells compared with SG611 and exerted synergistic cytotoxicity with low-dose daunorubicin (DNR) in vitro. In xenograft models, SG611-VSTM1 intratumorally injected at a dose of 1 × 10(9) plaque forming units combined with intraperitoneally injected low-dose DNR displayed significantly stronger antitumor effects than either treatment alone. Histopathologic examination revealed that SG611-VSTM1 induced apoptosis of leukemic cells. These results implicate an important role for VSTM1 in the pathogenesis of leukemia, and SG611-VSTM1 may be a promising agent for enhancing chemosensitivity in leukemia therapy.
authors.affiliation: Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Peking University People's Hospital and Institute of Hematology, 11 Xi-Zhi-Men South Street, Beijing, 100044, China.
authors.forename: Jiao
authors.initials: J
authors.lastname: Zhou
authors.affiliation: Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Peking University People's Hospital and Institute of Hematology, 11 Xi-Zhi-Men South Street, Beijing, 100044, China.
authors.forename: Qiu-Mei
authors.initials: QM
authors.lastname: Yao
authors.affiliation: Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Peking University People's Hospital and Institute of Hematology, 11 Xi-Zhi-Men South Street, Beijing, 100044, China.
authors.forename: Jin-Lan
authors.initials: JL
authors.lastname: Li
authors.affiliation: Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Peking University People's Hospital and Institute of Hematology, 11 Xi-Zhi-Men South Street, Beijing, 100044, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Chang
authors.affiliation: Key Laboratory of Medical Immunology, Department of Immunology, Ministry of Health, School of Basic Medical Sciences, Peking University Health Science Center, Peking University Center for Human Disease Genomics, 38 Xueyuan Road, Beijing, 100191, China.
authors.forename: Ting
authors.initials: T
authors.lastname: Li
authors.affiliation: Key Laboratory of Medical Immunology, Department of Immunology, Ministry of Health, School of Basic Medical Sciences, Peking University Health Science Center, Peking University Center for Human Disease Genomics, 38 Xueyuan Road, Beijing, 100191, China.
authors.forename: Wen-Ling
authors.initials: WL
authors.lastname: Han
authors.affiliation: Laboratory of Viral and Gene Therapy, Eastern Hepatobiliary Surgical Hospital, Second Military Medical University, 225 Changhai Road, Shanghai, 200438, China.
authors.forename: Hong-Ping
authors.initials: HP
authors.lastname: Wu
authors.affiliation: Laboratory of Viral and Gene Therapy, Eastern Hepatobiliary Surgical Hospital, Second Military Medical University, 225 Changhai Road, Shanghai, 200438, China.
authors.forename: Lin-Fang
authors.initials: LF
authors.lastname: Li
authors.affiliation: Laboratory of Viral and Gene Therapy, Eastern Hepatobiliary Surgical Hospital, Second Military Medical University, 225 Changhai Road, Shanghai, 200438, China.
authors.forename: Qi-Jun
authors.initials: QJ
authors.lastname: Qian
authors.affiliation: Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Peking University People's Hospital and Institute of Hematology, 11 Xi-Zhi-Men South Street, Beijing, 100044, China. ruanguorui@pkuph.edu.cn.
authors.forename: Guo-Rui
authors.initials: GR
authors.lastname: Ruan
mesh_terms: D000256:Adenoviridae / Q000235:genetics* / Q000502:physiology; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage*; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D003131:Combined Modality Therapy; D003630:Daunorubicin / Q000008:administration & dosage*; D005260:Female; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007938:Leukemia / Q000188:drug therapy / Q000503:physiopathology / Q000628:therapy* / Q000821:virology; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D050130:Oncolytic Virotherapy; D050504:Oncolytic Viruses / Q000235:genetics* / Q000502:physiology; D011971:Receptors, Immunologic / Q000235:genetics* / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D011971:Receptors, Immunologic; C550469:VSTM1 protein, human; D003630:Daunorubicin
keywords: Daunorubicin; Gene therapy; Leukemia; Oncolytic adenovirus; VSTM1 gene