title: Ablation of MCL1 expression by virally induced microRNA-29 reverses chemoresistance in human osteosarcomas.
abstract: Osteosarcoma is a rare disease diagnosed as malignant bone tumor. It is generally refractory to chemotherapy, which contributes to its poor prognosis. The reversal of chemoresistance is a major clinical challenge to improve the prognostic outcome of osteosarcoma patients. We developed a tumor-specific replication-competent oncolytic adenovirus, OBP-301 (telomelysin) and assessed its synergistic effects with chemotherapeutic agents (cisplatin and doxorubicin) using human osteosarcoma cell lines and a xenograft tumor model. The molecular mechanism underlying the chemosensitizing effect of OBP-301 was evaluated in aspects of apoptosis induction. OBP-301 inhibits anti-apoptotic myeloid cell leukemia 1 (MCL1) expression, which in turn leads to chemosensitization in human osteosarcoma cells. The siRNA-mediated knockdown of MCL1 expression sensitized human osteosarcoma cells to common chemotherapeutic agents. We also found that upregulation of microRNA-29 targeting MCL1 via virally induced transcriptional factor E2F-1 activation was critical for the enhancement of chemotherapy-induced apoptosis in osteosarcoma cells. Telomerase-specific oncolytic adenovirus synergistically suppressed the viability of human osteosarcoma cells in combination with chemotherapeutic agents. The combination treatment also significantly inhibited tumor growth, as compared to monotherapy, in an osteosarcoma xenograft tumor model. Our data suggest that replicative virus-mediated tumor-specific MCL1 ablation may be a promising strategy to attenuate chemoresistance in osteosarcoma patients.
authors.affiliation: Department of Orthopaedic Surgery, Okayama University, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama 700-8558, Japan.
authors.forename: Shuhei
authors.initials: S
authors.lastname: Osaki
authors.affiliation: Department of Gastroenterological Surgery, Okayama University, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama 700-8558, Japan.|Center for Innovative Clinical Medicine, Okayama University Hospital, Okayama 700-8558, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Tazawa
authors.affiliation: Department of Orthopaedic Surgery, Okayama University, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama 700-8558, Japan.
authors.forename: Joe
authors.initials: J
authors.lastname: Hasei
authors.affiliation: Department of Orthopaedic Surgery, Okayama University, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama 700-8558, Japan.
authors.forename: Yasuaki
authors.initials: Y
authors.lastname: Yamakawa
authors.affiliation: Department of Orthopaedic Surgery, Okayama University, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama 700-8558, Japan.
authors.forename: Toshinori
authors.initials: T
authors.lastname: Omori
authors.affiliation: Department of Orthopaedic Surgery, Okayama University, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama 700-8558, Japan.
authors.forename: Kazuhisa
authors.initials: K
authors.lastname: Sugiu
authors.affiliation: Department of Orthopaedic Surgery, Okayama University, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama 700-8558, Japan.
authors.forename: Tadashi
authors.initials: T
authors.lastname: Komatsubara
authors.affiliation: Department of Orthopaedic Surgery, Okayama University, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama 700-8558, Japan.|Center for Innovative Clinical Medicine, Okayama University Hospital, Okayama 700-8558, Japan.
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Fujiwara
authors.affiliation: Department of Orthopaedic Surgery, Okayama University, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama 700-8558, Japan.
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Sasaki
authors.affiliation: Department of Orthopaedic Surgery, Okayama University, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama 700-8558, Japan.|Department of Medical Materials for Musculoskeletal Reconstruction, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama 700-8558, Japan.
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Kunisada
authors.affiliation: Department of Orthopaedic Surgery, Okayama University, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama 700-8558, Japan.
authors.forename: Aki
authors.initials: A
authors.lastname: Yoshida
authors.affiliation: Oncolys BioPharma, Inc., Tokyo 105-0001, Japan.
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Urata
authors.affiliation: Department of Gastroenterological Surgery, Okayama University, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama 700-8558, Japan.
authors.forename: Shunsuke
authors.initials: S
authors.lastname: Kagawa
authors.affiliation: Department of Orthopaedic Surgery, Okayama University, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama 700-8558, Japan.
authors.forename: Toshifumi
authors.initials: T
authors.lastname: Ozaki
authors.affiliation: Department of Gastroenterological Surgery, Okayama University, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama 700-8558, Japan.
authors.forename: Toshiyoshi
authors.initials: T
authors.lastname: Fujiwara
mesh_terms: D000256:Adenoviridae / Q000235:genetics / Q000254:growth & development; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage*; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000008:administration & dosage; D004195:Disease Models, Animal; D004317:Doxorubicin / Q000008:administration & dosage; D004351:Drug Resistance; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors; D064593:Heterografts; D006801:Humans; D035683:MicroRNAs / Q000378:metabolism*; D064549:Myeloid Cell Leukemia Sequence 1 Protein / Q000037:antagonists & inhibitors*; D009368:Neoplasm Transplantation; D050504:Oncolytic Viruses / Q000235:genetics / Q000254:growth & development; D012516:Osteosarcoma / Q000473:pathology / Q000628:therapy*; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; C579095:MCL1 protein, human; C532045:MIRN29a microRNA, human; D035683:MicroRNAs; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D004317:Doxorubicin; D002945:Cisplatin