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

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

doi:10.3892/ijo.2015.3236

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

Authors:
- Yoshinobu Saitoh
- Takao Setoguchi
- Masahito Nagata
- Arisa Tsuru
- Shunsuke Nakamura
- Satoshi Nagano
- Yasuhiro Ishidou
- Hiroko Nagao-Kitamoto
- Masahiro Yokouchi
- Shingo Maeda
- Akihide Tanimoto
- Tatsuhiko Furukawa
- Setsuro Komiya
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Affiliations: Department of Orthopaedic Surgery, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima 890-8520, Japan, The Near-Future Locomotor Organ Medicine Creation Course (Kusunoki Kai), Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima 890-8520, Japan, Department of Medical Joint Materials, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima 890-8520, Japan, Center for the Research of Advanced Diagnosis and Therapy of Cancer, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima 890-8520, Japan
Published online on: November 6, 2015 https://doi.org/10.3892/ijo.2015.3236
Pages: 235-242

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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.

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