title: Combination of Hedgehog inhibitors and standard anticancer agents synergistically prevent osteosarcoma growth.
abstract: High-dose chemotherapy and surgical intervention have improved long-term prognosis for non-metastatic osteosarcoma to 50-80%. However, metastatic osteosarcoma exhibits resistance to standard chemotherapy. We and others have investigated the function of Hedgehog pathway in osteosarcoma. To apply our previous findings in clinical settings, we examined the effects of Hedgehog inhibitors including arsenic trioxide (ATO) and vismodegib combined with standard anticancer agents. We performed WST-1 assays using ATO, cisplatin (CDDP), ifosfamide (IFO), doxorubicin (DOX), and vismodegib. Combination-index (CI) was used to examine synergism using CalcuSyn software. Xenograft models were used to examine the synergism in vivo. WST-1 assays showed that 143B and Saos2 cell proliferation was inhibited by ATO combined with CDDP, IFO, DOX, and vismodegib. Combination of ATO and CDDP, IFO, DOX or vismodegib was synergistic when the two compounds were used on proliferating 143B and Saos2 human osteosarcoma cells. An osteosarcoma xenograft model showed that treatment with ATO and CDDP, IFO, or vismodegib significantly prevented osteosarcoma growth in vivo compared with vehicle treatment. Our findings indicate that combination of Hedgehog pathway inhibitors and standard FDA-approved anticancer agents with established safety for human use may be an attractive therapeutic method for treating osteosarcoma.
authors.affiliation: Department of Orthopaedic Surgery, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima 890-8520, Japan.
authors.forename: Yoshinobu
authors.initials: Y
authors.lastname: Saitoh
authors.affiliation: The Near-Future Locomotor Organ Medicine Creation Course (Kusunoki Kai), Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima 890-8520, Japan.
authors.forename: Takao
authors.initials: T
authors.lastname: Setoguchi
authors.affiliation: Department of Orthopaedic Surgery, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima 890-8520, Japan.
authors.forename: Masahito
authors.initials: M
authors.lastname: Nagata
authors.affiliation: Department of Orthopaedic Surgery, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima 890-8520, Japan.
authors.forename: Arisa
authors.initials: A
authors.lastname: Tsuru
authors.affiliation: Department of Orthopaedic Surgery, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima 890-8520, Japan.
authors.forename: Shunsuke
authors.initials: S
authors.lastname: Nakamura
authors.affiliation: Department of Orthopaedic Surgery, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima 890-8520, Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Nagano
authors.affiliation: Department of Medical Joint Materials, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima 890-8520, Japan.
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Ishidou
authors.affiliation: Department of Orthopaedic Surgery, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima 890-8520, Japan.
authors.forename: Hiroko
authors.initials: H
authors.lastname: Nagao-Kitamoto
authors.affiliation: Department of Orthopaedic Surgery, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima 890-8520, Japan.
authors.forename: Masahiro
authors.initials: M
authors.lastname: Yokouchi
authors.affiliation: Department of Medical Joint Materials, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima 890-8520, Japan.
authors.forename: Shingo
authors.initials: S
authors.lastname: Maeda
authors.affiliation: Center for the Research of Advanced Diagnosis and Therapy of Cancer, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima 890-8520, Japan.
authors.forename: Akihide
authors.initials: A
authors.lastname: Tanimoto
authors.affiliation: Center for the Research of Advanced Diagnosis and Therapy of Cancer, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima 890-8520, Japan.
authors.forename: Tatsuhiko
authors.initials: T
authors.lastname: Furukawa
authors.affiliation: Department of Orthopaedic Surgery, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima 890-8520, Japan.
authors.forename: Setsuro
authors.initials: S
authors.lastname: Komiya
mesh_terms: D000813:Anilides / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage*; D017209:Apoptosis / Q000187:drug effects; D000077237:Arsenic Trioxide; D001152:Arsenicals / Q000008:administration & dosage; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002945:Cisplatin / Q000008:administration & dosage; D004317:Doxorubicin / Q000008:administration & dosage; D004357:Drug Synergism; D053823:Hedgehog Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics; D006801:Humans; D012516:Osteosarcoma / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D010087:Oxides / Q000008:administration & dosage; D011725:Pyridines / Q000008:administration & dosage
chemical_list: D000813:Anilides; D001152:Arsenicals; D053823:Hedgehog Proteins; C538724:HhAntag691; D010087:Oxides; D011725:Pyridines; D004317:Doxorubicin; D002945:Cisplatin; D000077237:Arsenic Trioxide