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  • Original Paper
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Oxamflatin is a novel antitumor compound that inhibits mammalian histone deacetylase

Oncogene volume 18, pages 2461–2470 (1999)Cite this article

Abstract

Oxamflatin [(2E) - 5 - [3 - [(phenylsufonyl) amino] phenyl]-pent-2-en-4-ynohydroxamic acid] induces transcriptional activation of junD and morphological reversion in various NIH3T3-derived transformed cell lines. We found that oxamflatin showed in vitro antiproliferative activity against various mouse and human tumor cell lines with drastic changes in the cell morphology and in vivo antitumor activity against B16 melanoma. Oxamflatin caused an elongated cell shape with filamentous protrusions as well as arrest of the cell cycle at the G1 phase in HeLa cells. These phenotypic changes of HeLa cells were apparently similar to those by trichostatin A (TSA), a specific inhibitor of histone deacetylase (HDAC). The effect of oxamflatin on the transcriptional activity of the cytomegalovirus (CMV) promoter was examined and compared with known HDAC inhibitors, TSA, sodium n-butyrate, and FR901228. Oxamflatin as well as all these inhibitors greatly enhanced the transcriptional activity of the CMV promoter in a dose-dependent manner. Oxamflatin, like TSA, inhibited intracellular HDAC activity, as a result of which marked amounts of acetylated histone species accumulated. Finally, effects on expression of several endogenous genes involved in cell morphology and cell cycle control in HeLa cells were analysed. Expression of gelsolin, cyclin E and Cdk inhibitors including p21WAF1/Cip1 was highly augmented, while that of cyclin A and cyclin D1 was decreased by oxamflatin. These results suggest that changes in the expression pattern of the genes regulating cell morphology and the cell cycle due to histone hyperacetylation are responsible for the antitumor activity, the morphological change and the cell cycle arrest induced by oxamflatin.

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Acknowledgements

We would like to thank D Kasuga, Tokyo Medical and Dental University for the gift of the cell lines. We are grateful to H Nakajima and K Shimomura, Fujisawa Pharmaceutical Co. Ltd., for providing us with FR901228. We would also like to thank SW Ki and S Akakura, the University of Tokyo, for helpful advice and discussion. This work was supported in part by a special grant for Advanced Research on Cancer from the Ministry of Education, Culture and Science of Japan to MY. YBK was supported by a scholarship from the Park Yong Koo Scholarship Foundation.

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  1. Department of Biotechnology, Graduate School of Agriculture and Life Sciences, The University of Tokyo, Bunkyo-ku, Tokyo, 113, Japan

    Young Bae Kim, Kun-Hyung Lee, Minoru Yoshida & Sueharu Horinouchi

  2. Shionogi Research Laboratories, Shionogi and Co., Ltd.,, Sagisu 5-12-4, Hukushima-ku, Osaka, 533, Japan

    Kenji Sugita

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Kim, Y., Lee, KH., Sugita, K. et al. Oxamflatin is a novel antitumor compound that inhibits mammalian histone deacetylase. Oncogene 18, 2461–2470 (1999). https://doi.org/10.1038/sj.onc.1202564

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