Busulfan inhibits growth of human osteosarcoma through miR‐200 family microRNAs in vitro and in vivo

• Published in: Cancer science Vol. 105; no. 7; pp. 755 - 762
• Main Authors: Mei, Qiang, Li, Fang, Quan, Hongyu, Liu, Yunlai, Xu, Haidong
• Format: Journal Article
• Language: English
• Published: England Blackwell Publishing Ltd 01.07.2014
• Subjects: Animals; Antineoplastic Agents, Alkylating - pharmacology; Apoptosis - drug effects; Bone Neoplasms - drug therapy; Bone Neoplasms - genetics; Bone Neoplasms - pathology; Busulfan; Busulfan - pharmacology; Cell Line, Tumor - drug effects; Cell Survival - drug effects; Dose-Response Relationship, Drug; Gene Expression Regulation, Neoplastic; Homeodomain Proteins - genetics; Homeodomain Proteins - metabolism; Humans; Male; Mice; Mice, Nude; microRNAs; MicroRNAs - genetics; Original; osteosarcoma; Osteosarcoma - drug therapy; Osteosarcoma - genetics; Osteosarcoma - pathology; Reactive Oxygen Species - metabolism; Repressor Proteins - genetics; Repressor Proteins - metabolism; Transcription Factors - genetics; Transcription Factors - metabolism; Up-Regulation - drug effects; Xenograft Model Antitumor Assays; ZEB1; ZEB2; Zinc Finger E-box Binding Homeobox 2; Zinc Finger E-box-Binding Homeobox 1; microRNAs; ZEB2; ZEB1; Busulfan; osteosarcoma
• ISSN: 1347-9032; 1349-7006
• DOI: 10.1111/cas.12436

Osteosarcoma typically arises in tissues of mesenchymal origin, and is the most malignant bone tumor characterized by high local aggressiveness, with poor therapeutic outcome. Busulfan has been widely used to treat CML. So far, there are no reports on the therapeutic effect of busulfan on osteosarcoma. Here, we showed that busulfan dose‐dependently reduced the cell viability and proliferation, and induced cell apoptosis, senescence, and reactive oxygen species levels in two osteosarcoma cell lines. Moreover, a series of loss‐of‐function and gain‐of‐function experiments further indicated that busulfan may have its anti‐osteosarcoma effect by upregulating the microRNA‐200 (miR‐200) family which subsequently downregulated its target genes ZEB1 and ZEB2. Furthermore, treatment with busulfan potentially inhibited the growth of implanted osteosarcoma in nude mice. Taken together, our data suggest that busulfan may have an anti‐osteosarcoma effect through downregulating ZEB1 and ZEB2 through activating the miR‐200 family, highlighting a possibility of using busulfan as a novel therapy for osteosarcoma. Busulfan may have its anti‐osteosarcoma effect via downregulating ZEB1 and ZEB2 through activating microRNA‐200 family, highlighting a possibility of using Busulfan as a novel therapy for osteosarcoma.