title: STAT3 inhibitor, cucurbitacin I, is a novel therapeutic agent for osteosarcoma.
abstract: The development of clinical agents remains a costly and time-consuming process. Although identification of new uses of existing drugs has been recognized as a more efficient approach for drug discovery than development of novel drugs, little screening of drugs that might be used for a rare malignant tumor such as osteosarcoma (OS) has been performed. In this study, we attempted to identify new molecular targeted agents for OS by employing Screening Committee of Anticancer Drugs (SCADS) kits. To screen compounds for OS treatment, their effect on cell viability of the OS cell lines 143B, MG63, HOS, SAOS-2, and HUO9 were evaluated. Candidate drugs were narrowed down based on a global anti-proliferative effect against these five OS cell lines. After excluding cytotoxic compounds and compounds unsuitable for in vivo administration, cucurbitacin I was extracted. Cucurbitacin I has been found to have cytotoxic and anti-proliferative properties against several tumors through inhibition of signal transducer and activator of transcription 3 (STAT3) activation. Cucurbitacin I dose- and time-dependently inhibited the proliferation of all five OS cell lines. Following cucurbitacin I treatment, STAT3 was inactivated and analysis of Mcl-1, cleaved PARP and caspase-3 indicated apoptosis induction. Expression of cell cycle regulator proteins, such as phospho-cyclin D1, c-Myc and survivin, were suppressed. Finally, cucurbitacin I potently inhibited the tumor growth of human OS 143B cells in nude mice. Our in vitro and in vivo results suggest that STAT3 inhibition by cucurbitacin I will be an effective and new approach for the treatment of OS.
authors.affiliation: Department of Orthopedic Surgery, Mie University School of Medicine, Tsu, Mie 514-8507, Japan.
authors.forename: Toru
authors.initials: T
authors.lastname: Oi
authors.affiliation: Department of Orthopedic Surgery, Mie University School of Medicine, Tsu, Mie 514-8507, Japan.
authors.forename: Kunihiro
authors.initials: K
authors.lastname: Asanuma
authors.affiliation: Department of Orthopedic Surgery, Mie University School of Medicine, Tsu, Mie 514-8507, Japan.
authors.forename: Akihiko
authors.initials: A
authors.lastname: Matsumine
authors.affiliation: Department of Orthopedic Surgery, Mie University School of Medicine, Tsu, Mie 514-8507, Japan.
authors.forename: Takao
authors.initials: T
authors.lastname: Matsubara
authors.affiliation: Department of Orthopedic Surgery, Mie University School of Medicine, Tsu, Mie 514-8507, Japan.
authors.forename: Tomoki
authors.initials: T
authors.lastname: Nakamura
authors.affiliation: Department of Orthopedic Surgery, Mie University School of Medicine, Tsu, Mie 514-8507, Japan.
authors.forename: Takahiro
authors.initials: T
authors.lastname: Iino
authors.affiliation: Department of Orthopedic Surgery, Mie University School of Medicine, Tsu, Mie 514-8507, Japan.
authors.forename: Yumiko
authors.initials: Y
authors.lastname: Asanuma
authors.affiliation: Department of Orthopedic Surgery, Mie University School of Medicine, Tsu, Mie 514-8507, Japan.
authors.forename: Mikinobu
authors.initials: M
authors.lastname: Goto
authors.affiliation: Department of Orthopedic Surgery, Mie University School of Medicine, Tsu, Mie 514-8507, Japan.
authors.forename: Kazuma
authors.initials: K
authors.lastname: Okuno
authors.affiliation: Department of Orthopedic Surgery, Mie University School of Medicine, Tsu, Mie 514-8507, Japan.
authors.forename: Takuya
authors.initials: T
authors.lastname: Kakimoto
authors.affiliation: Department of Orthopedic Surgery, Mie University School of Medicine, Tsu, Mie 514-8507, Japan.
authors.forename: Yuki
authors.initials: Y
authors.lastname: Yada
authors.affiliation: Department of Orthopedic Surgery, Mie University School of Medicine, Tsu, Mie 514-8507, Japan.
authors.forename: Akihiro
authors.initials: A
authors.lastname: Sudo
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001859:Bone Neoplasms / Q000188:drug therapy* / Q000473:pathology; D053148:Caspase 3 / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects; D019938:Cyclin D1 / Q000378:metabolism; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D064549:Myeloid Cell Leukemia Sequence 1 Protein / Q000378:metabolism; D012516:Osteosarcoma / Q000188:drug therapy* / Q000473:pathology; D000071137:Poly (ADP-Ribose) Polymerase-1 / Q000378:metabolism; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D000077022:Survivin; D014315:Triterpenes / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; C107489:BIRC5 protein, human; C530104:CCND1 protein, human; D051034:Inhibitor of Apoptosis Proteins; C579095:MCL1 protein, human; C489427:MYC protein, human; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D016271:Proto-Oncogene Proteins c-myc; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D000077022:Survivin; D014315:Triterpenes; D019938:Cyclin D1; C499320:PARP1 protein, human; D000071137:Poly (ADP-Ribose) Polymerase-1; D053148:Caspase 3; C038106:cucurbitacin I