Combination of Hedgehog inhibitors and standard anticancer agents synergistically prevent osteosarcoma growth

• Published in: International journal of oncology Vol. 48; no. 1; pp. 235 - 242
• Main Authors: SAITOH, YOSHINOBU, SETOGUCHI, TAKAO, NAGATA, MASAHITO, TSURU, ARISA, NAKAMURA, SHUNSUKE, NAGANO, SATOSHI, ISHIDOU, YASUHIRO, NAGAO-KITAMOTO, HIROKO, YOKOUCHI, MASAHIRO, MAEDA, SHINGO, TANIMOTO, AKIHIDE, FURUKAWA, TATSUHIKO, KOMIYA, SETSURO
• Format: Journal Article
• Language: English
• Published: Greece D.A. Spandidos 01-01-2016; Spandidos Publications; Spandidos Publications UK Ltd
• Subjects: Anilides - administration & dosage; Antineoplastic Combined Chemotherapy Protocols - administration & dosage; Apoptosis - drug effects; arsenic trioxide; Arsenicals - administration & dosage; Bone cancer; Cell growth; Cell Line, Tumor; Cell Proliferation - drug effects; Chemotherapy; Cisplatin - administration & dosage; Development and progression; Doxorubicin - administration & dosage; Drug dosages; Drug Synergism; FDA approval; Gene expression; Genetic aspects; GLI2; Health aspects; Hedgehog; Hedgehog proteins; Hedgehog Proteins - antagonists & inhibitors; Hedgehog Proteins - genetics; Humans; Laboratory animals; Metastasis; Osteosarcoma; Osteosarcoma - drug therapy; Osteosarcoma - genetics; Osteosarcoma - pathology; Oxides - administration & dosage; Pyridines - administration & dosage; Sarcoma; United States > US; Japan
• ISSN: 1019-6439; 1791-2423
• DOI: 10.3892/ijo.2015.3236

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.