期刊
INTERNATIONAL JOURNAL OF ONCOLOGY
卷 48, 期 1, 页码 235-242出版社
SPANDIDOS PUBL LTD
DOI: 10.3892/ijo.2015.3236
关键词
arsenic trioxide; osteosarcoma; Hedgehog; GLI2
类别
资金
- KAKENHI [19591725, 20591786, 21591919, 21591920, 22591663, 23592195]
- Ministry of Health, Labour and Welfare of Japan for the Third Term Comprehensive Control Research for Cancer
- [201201976]
- Grants-in-Aid for Scientific Research [23592195, 22591663, 20591786, 21591920, 21591919] Funding Source: KAKEN
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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