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FR901228 induces tumor regression associated with induction of Fas ligand and activation of Fas signaling in human osteosarcoma cells

Oncogene volume 22, pages 9231–9242 (2003)Cite this article

Abstract

We investigated the antitumor effects of FR901228, a HDAC inhibitor, on human osteosarcoma cells, in vitro and in vivo to explore its possible utility in the treatment of pediatric bone cancers. FR901228 caused marked growth inhibition with a 50% inhibitory concentration of 1.2–7.3 nM and induction of apoptosis in all eight osteosarcoma cell lines tested. These effects of FR901228 were also observed in vivo xenograft models on BALB/c nude mice, and treatment with 5.6 mg/kg/day resulting in a >70% reduction in the mean final tumor volume compared with the mean initial tumor volume. TUNEL assays demonstrated extensive apoptosis in tumor sections of mice treated with FR901228. Induction of apoptosis was preceded by increased expression of Fas ligand (FasL) mRNA, resulting in expression of membrane-bound FasL, which was followed by sequential activation of caspase-8 and -3. The level of apoptosis induction was reduced using a neutralizing anti-FasL antibody and overexpression of either the dominant-negative FADD or the viral FLICE inhibitory protein. Furthermore, treatment with a suboptimal dose of FR901228 greatly sensitized osteosarcoma cells to agonistic anti-Fas antibody-mediated apoptosis. These findings suggest that FR901228 is a highly promising antitumor agent against osteosarcoma, inducing apoptosis by the activation of the Fas/FasL system.

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Acknowledgements

We are grateful to Dr Yasuaki Nakajima (Laboratory of Anatomic Pathology, Kyoto University) for helpful discussion and Kyoko Maruyama for technical assistance. This work was supported by a Grant-in-Aid for Scientific Research on Priority Areas (12215067) and by a Grant-in-Aid for Creative Scientific Research (13GS0009) from the Ministry of Education, Culture, Sports, Science, and Technology of Japan.

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Authors and Affiliations

  1. Department of Pediatrics, Graduate School of Medicine, Kyoto University, 54 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto, 606-8507, Japan

    Tsuyoshi Imai, Souichi Adachi, Masayuki Okada, Takahiro Yasumi, Ken-ichiro Watanabe, Ryuta Nishikomori & Tatsutoshi Nakahata

  2. Department of Orthopaedic Surgery, Graduate School of Medicine, Kyoto University, 54 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto, 606-8507, Japan

    Koichi Nishijo & Tomitaka Nakayama

  3. Graduate School of Biostudies and Institute for Virus Research, Kyoto University, 53 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto, 606-8507, Japan

    Masatoshi Ohgushi & Shin Yonehara

  4. Graduate School of Medicine and Institute for Frontier Medical Science, Kyoto University, 53 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto, 606-8507, Japan

    Junya Toguchida

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Correspondence to Souichi Adachi.

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Imai, T., Adachi, S., Nishijo, K. et al. FR901228 induces tumor regression associated with induction of Fas ligand and activation of Fas signaling in human osteosarcoma cells. Oncogene 22, 9231–9242 (2003). https://doi.org/10.1038/sj.onc.1207184

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