title: Combination therapy with bioengineered miR-34a prodrug and doxorubicin synergistically suppresses osteosarcoma growth.
abstract: Osteosarcoma (OS) is the most common form of primary malignant bone tumor and prevalent among children and young adults. Recently we have established a novel approach to bioengineering large quantity of microRNA-34a (miR-34a) prodrug for miRNA replacement therapy. This study is to evaluate combination treatment with miR-34a prodrug and doxorubicin, which may synergistically suppress human OS cell growth via RNA interference and DNA intercalation. Synergistic effects were indeed obvious between miR-34a prodrug and doxorubicin for the suppression of OS cell proliferation, as defined by Chou-Talalay method. The strongest antiproliferative synergism was achieved when both agents were administered simultaneously to the cells at early stage, which was associated with much greater degrees of late apoptosis, necrosis, and G2 cell cycle arrest. Alteration of OS cellular processes and invasion capacity was linked to the reduction of protein levels of miR-34a targeted (proto-)oncogenes including SIRT1, c-MET, and CDK6. Moreover, orthotopic OS xenograft tumor growth was repressed to a significantly greater degree in mouse models when miR-34a prodrug and doxorubicin were co-administered intravenously. In addition, multiple doses of miR-34a prodrug and doxorubicin had no or minimal effects on mouse blood chemistry profiles. The results demonstrate that combination of doxorubicin chemotherapy and miR-34a replacement therapy produces synergistic antiproliferative effects and it is more effective than monotherapy in suppressing OS xenograft tumor growth. These findings support the development of mechanism-based combination therapy to combat OS and bioengineered miR-34a prodrug represents a new natural miRNA agent.
authors.affiliation: Department of Orthopedics, Zhongnan Hospital of Wuhan University, Wuhan, Hubei 430070, China; Department of Biochemistry & Molecular Medicine, UC Davis School of Medicine, Sacramento, CA 95817, USA.
authors.forename: Yong
authors.initials: Y
authors.lastname: Zhao
authors.affiliation: Department of Biochemistry & Molecular Medicine, UC Davis School of Medicine, Sacramento, CA 95817, USA.
authors.forename: Mei-Juan
authors.initials: MJ
authors.lastname: Tu
authors.affiliation: Department of Orthopedics, Zhongnan Hospital of Wuhan University, Wuhan, Hubei 430070, China.
authors.forename: Yi-Feng
authors.initials: YF
authors.lastname: Yu
authors.affiliation: Department of Biochemistry & Molecular Medicine, UC Davis School of Medicine, Sacramento, CA 95817, USA.
authors.forename: Wei-Peng
authors.initials: WP
authors.lastname: Wang
authors.affiliation: Department of Biochemistry & Molecular Medicine, UC Davis School of Medicine, Sacramento, CA 95817, USA.
authors.forename: Qiu-Xia
authors.initials: QX
authors.lastname: Chen
authors.affiliation: Department of Pathology, Roswell Park Cancer Institute, Buffalo, NY 14263, USA.
authors.forename: Jing-Xin
authors.initials: JX
authors.lastname: Qiu
authors.affiliation: Department of Orthopedics, Zhongnan Hospital of Wuhan University, Wuhan, Hubei 430070, China. Electronic address: yuaixi@whu.edu.cn.
authors.forename: Ai-Xi
authors.initials: AX
authors.lastname: Yu
authors.affiliation: Department of Biochemistry & Molecular Medicine, UC Davis School of Medicine, Sacramento, CA 95817, USA. Electronic address: aimyu@ucdavis.edu.
authors.forename: Ai-Ming
authors.initials: AM
authors.lastname: Yu
mesh_terms: D000818:Animals; D057005:Bioengineering / Q000379:methods*; D001859:Bone Neoplasms / Q000188:drug therapy* / Q000473:pathology; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000008:administration & dosage*; D004359:Drug Therapy, Combination; D006131:Growth Inhibitors / Q000008:administration & dosage; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D035683:MicroRNAs / Q000008:administration & dosage*; D009361:Neoplasm Invasiveness / Q000473:pathology / Q000517:prevention & control; D012516:Osteosarcoma / Q000188:drug therapy* / Q000473:pathology; D011355:Prodrugs / Q000008:administration & dosage*; D023041:Xenograft Model Antitumor Assays / Q000379:methods
chemical_list: D006131:Growth Inhibitors; C522425:MIRN34 microRNA, human; D035683:MicroRNAs; D011355:Prodrugs; D004317:Doxorubicin
keywords: Chemotherapy; Doxorubicin; Orthotopic tumor; Osteosarcoma; miR-34a