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Arsenic Trioxide Prevents Osteosarcoma Growth by Inhibition of GLI Transcription via DNA Damage Accumulation Nakamura, Shunsuke ナカムラ, シュンスケ 中村, 俊介 Nagano, Satoshi ナガノ, サトシ 永野, 聡 Nagao, Hiroko ナガオ, ヒロコ 永尾, 宗子 Ishidou, Yasuhiro イシドウ, ヤスヒロ 石堂, 康弘 Yokouchi, Masahiro ヨコウチ, マサヒロ 横内, 雅博 棈松, 昌彦 アベマツ, マサヒコ Abematsu, Masahiko Yamamoto, Takuya ヤマモト, タクヤ 山元, 拓哉 Komiya, Setsuro コミヤ, セツロウ 小宮, 節郎 Setoguchi, Takao セトグチ, タカオ 瀬戸口, 啓夫 open access © 2013 Nakamura et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. The Hedgehog pathway is activated in various types of malignancies. We previously reported that inhibition of SMO or GLI prevents osteosarcoma growth in vitro and in vivo. Recently, it has been reported that arsenic trioxide (ATO) inhibits cancer growth by blocking GLI transcription. In this study, we analyzed the function of ATO in the pathogenesis of osteosarcoma. Real-time PCR showed that ATO decreased the expression of Hedgehog target genes, including PTCH1, GLI1, and GLI2, in human osteosarcoma cell lines. WST-1 assay and colony formation assay revealed that ATO prevented osteosarcoma growth. These findings show that ATO prevents GLI transcription and osteosarcoma growth in vitro. Flow cytometric analysis showed that ATO promoted apoptotic cell death. Comet assay showed that ATO treatment increased accumulation of DNA damage. Western blot analysis showed that ATO treatment increased the expression of γH2AX, cleaved PARP, and cleaved caspase-3. In addition, ATO treatment decreased the expression of Bcl-2 and Bcl-xL. These findings suggest that ATO treatment promoted apoptotic cell death caused by accumulation of DNA damage. In contrast, Sonic Hedgehog treatment decreased the expression of γH2AX induced by cisplatin treatment. ATO re-induced the accumulation of DNA damage attenuated by Sonic Hedgehog treatment. These findings suggest that ATO inhibits the activation of Hedgehog signaling and promotes apoptotic cell death in osteosarcoma cells by accumulation of DNA damage. Finally, examination of mouse xenograft models showed that ATO administration prevented the growth of osteosarcoma in nude mice. Because ATO is an FDA-approved drug for treatment of leukemia, our findings suggest that ATO is a new therapeutic option for treatment of patients with osteosarcoma. Public Library of Science 2013-07-08 eng journal article VoR http://hdl.handle.net/10232/19918 https://ir.kagoshima-u.ac.jp/records/11595 https://doi.org/10.1371/journal.pone.0069466 19326203 PLoS ONE 8 7 https://ir.kagoshima-u.ac.jp/record/11595/files/Arsenic Trioxide Prevents Osteosarcoma Growth by Inhibition of GLI Transcription via DNA Damage Accumulation.pdf application/pdf 2.4 MB 2016-10-31 2013-07-08