Novel histone deacetylase inhibitor exhibits antitumor activity via apoptosis induction in oral squamous cell carcinoma

Abstract

Epigenetic modifications such as histone deacetylation are commonly related to tumor development and histone deacetylase (HDAC) inhibitors have been shown to be potential drugs for cancer treatment. In the present study, we investigated the effects of a novel HDAC inhibitor, Ky-2, on oral squamous carcinoma cells in vitro. Cell viability was significantly reduced by treatment with Ky-2 at 25 nM, while it also led to augmentation of the proportion of cells in the sub-G1 phase and DNA fragmentation. In addition, immunoblot analysis revealed that Ky-2 enhanced the expression of apoptosis-related proteins. Our results showed that a low concentration of Ky-2 induced apoptosis in oral squamous carcinoma cells via activation of apoptotic cascades.

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Takahashi, O. , Okinaga, T. , Iwanaga, K. , Habu, M. , Ariyoshi, W. , Tominaga, K. , Nishino, N. and Nishihara, T. (2011) Novel histone deacetylase inhibitor exhibits antitumor activity via apoptosis induction in oral squamous cell carcinoma. Journal of Biophysical Chemistry, 2, 215-221. doi: 10.4236/jbpc.2011.23026.

Conflicts of Interest

The authors declare no conflicts of interest.

References

[1] Shen, J., Huang, C., Jiang, L., Gao, F., Wang, Z., Zhang, Y., Bai, J., Zhou, H. and Chen, Q. (2007) Enhancement of cisplatin induced apoptosis by suberoylanilide hydroxamic acid in human oral squamous cell carcinoma cell lines. Biochemical Pharmacology, 73, 1901-1909. doi:10.1016/j.bcp.2007.03.009
[2] Nagumo, T., Takaoka S., Yoshiba, S., Ohashi, M., Shirota, T., Hatori, M., Isobe, T., Tachikawa, T. and Sintani, S. (2009) Antitumor activity of suberoylanilide hydroxamic acid against human oral squamous cell carcinoma cell lines in vitro and in vivo. Oral Oncology, 45, 766-770. doi:10.1016/j.oraloncology.2008.11.009
[3] Ouwehand, K., de Ruijter, A.J.M., Van Bree, C., Caron, H.N. and Van Kuilenburg, A.B.P. (2005) Histone deacetylase inhibitor BL1521 induces a G1-phase arrest in neuroblastoma cells through altered expression of cell cycle proteins. FEBS Letter, 579, 1523-1528. doi:10.1016/j.febslet.2005.01.058
[4] Gillenwater, A.M., Zhong, M. and Lotan, R. (2007) Histone deacetylase inhibitor suberoylanilide hydroxamic acid induces apoptosis through both mitochondrial and Fas (Cd95) signaling in head and neck squamous carcinoma cells. Molecular Cancer Therapeutics, 6, 2967- 2975. doi:10.1158/1535-7163.MCT-04-0344
[5] Germain, C.T., O’Brien, A. and Dimitroulakos, J. (2010) Activating transcription factor 3 regulates in part enhanced tumour cell cytotoxicity of the histone deacetylase inhibitor M344 and cisplatin in combination. Cancer Cell International, 10, 32-43. doi:10.1186/1475-2867-10-32
[6] Carew, J.S., Giles, F.J. and Nawrocki, S.T. (2008) Histone deacetylase inhibitors: Mechanisms of cell death and promise in combination cancer therapy. Cancer Letter, 269, 7-17. doi:10.1016/j.canlet.2008.03.037
[7] Tang, Y.A., Wen, W.L., Chang, J.W., Wei, T.T., Tan, Y.H.C., Salunke, S., Chen, C.T., Chen, C.S. and Wang, Y.C. (2010) A novel histone deacetylase inhibitor exhibits antitumor activity via apoptosis induction, F-Actin disruption and gene acetylation in lung cancer. PloS One, 5, e12417. doi:10.1371/journal.pone.0012417
[8] Furumai, R., Komatsu, Y., Nishino, N., Khochbin, S., Yoshida, M. and Horinouchi, S. (2001) Potent histone deacetylase inhibitors built from trichostatin A and cyclic tetrapeptide antibiotics including trapoxin. Proceedings of the National Academy of Sciences USA, 98, 87-92. doi:10.1073/pnas.011405598
[9] Kim, D.H., Kim, M. and Kwon, H.J. (2003) Histone deacetylase in carcinogenesis and its inhibitors as anti-cancer agents. Journal of Biochemistry and Molecular Biology, 36, 110-119. doi:10.5483/BMBRep.2003.36.1.110
[10] Jhonstone, R.W. (2002) Histone-deacetylase inhibitors: Novel drugs for the treatment of cancer. Nature Reviews Drug Discovery, 1, 287-299. doi:10.1038/nrd772
[11] Lee, J.H., Choy, M.L., Ngo, L., Foster, S.S. and Marks, P.A. (2010) Histone deacetylase inhibitor induces DNA damage, which normal but not transformed cells can repair. Proceedings of the National Academy of Sciences USA, 107, 14639-14644. doi:10.1073/pnas.1008522107
[12] Kelly, W.K., O’Connor, O.A., Krug, L.M., Chiao, J.H., Heaney, M., Curley, T., MacGregore-Cortelli, B., Tong, W., Secrist, J.P., Richardson, S.S., Chu, E., Olgac, S., Marks, P.A., Scher, H. and Richon, V.M. (2005) Phase I study of an oral histone deacetylase inhibitor, suberoylanilide hydroxamic acid, in patients with advanced cancer. Journal of Clinical Oncology, 23, 3923-3931. doi:10.1200/JCO.2005.14.167
[13] Johnstone, R.W. (2002) Histone-deacetylase inhibitors: Novel drugs for the treatment of cancer. Nature Reviews Drug Discovery, 1, 287-299. doi:10.1038/nrd772
[14] Huang, L. and Pardee, A.B. (2000) Suberoylanilide hydroxamic acid as a potential therapeutic agent for human breast cancer treatment. Molecular Medicine, 6, 849-866
[15] Oiso, H., Furukawa, N., Suefuji, M., Shimoda, S., Ito, A., Furumai, R., Nakagawa, J., Yoshida, M., Nishino, N. and Araki, E. (2010) The role of class I histone deacetylase (HDAC) on gluconeogenesis in liver. Biochemical Biophysical Research Communications, 404, 166-072. doi:10.1016/j.bbrc.2010.11.086
[16] Komatsu, Y., Tomizaki, K., Tsukamoto, M., Kato, T., Nishino, N., Sato, S., Yamori, T., Tsuruo, T., Furumai, R., Yoshida, M., Horinouchi, S. and Hayashi, H. (2001) Cyclic hydroxamic-acid-containing peptide 31, a potent synthetic histone deacetylase inhibitor with antitumor activity. Cancer Research, 61, 4459-4466.
[17] Finnin, M.S., Donigian, J.R., Cohen, A., Richon, V.M., Rifkind, R.A., Marks, P.A., Breslow, R. and Pavletich, N.P. (1999) Structures of a histone deacetylase homologue bound to the TSA and SAHA inhibitors. Nature, 401, 188-193. doi:10.1038/43710
[18] Peart, M.J., Tainton, K.M., Ruefli, A.A., Dear, A.E., Sedelies, K.A., O’Reilly, L.A., Waterhouse, N.J., Trapani, J.A. and Johnstone, R.W. (2003) Novel mechanisms of apoptosis induced by histone deacetylase inhibitors. Cancer Research, 63, 4460-4471.
[19] De Schepper, S., Bruwiere, H., Verhulst, T., Steller, U., Andries, L., Wouters, W., Janicot, M., Arts, J. and Van Heusden, J. (2003) Inhibition of histone deacetylases by chlamydocin induces apoptosis and proteasome-mediated degradation of surviving. Journal of Pharmacology and Experimental Therapeutics, 304, 881-888. doi:10.1124/jpet.102.042903
[20] Okinaga, T., Kasai H., Tsujisawa, T. and Nishihara, T. (2007) Role of caspases in cleavage of lamin A/C and PARP during apoptosis in macrophages infected with a periodontopathic bacterium. Journal of Medical Microbiology, 56, 1399-1404. doi:10.1099/jmm.0.47193-0
[21] Kok, S.H., Cheng, S.J., Hong, C.Y., Lee, J.J., Lin, S.K., Kuo, Y.S., Chiang, C.P. and Kuo, M.Y.P. (2005) Norcantharidin-induced apoptosis in oral cancer cells is associated with an increase of proapoptotic to antiapoptotic protein ratio. Cancer Letter, 217, 43-52. doi:10.1016/j.canlet.2004.07.045
[22] Henderson, C., Mizzau, M., Paroni, G., Maesyro, R., Schneider, C. and Brancolini, C. (2003) Role of caspases, Bid, and p53 in the apoptotic response triggered by histone deacetylase inhibitors Trichostatin-A (TSA) and Suberoylanilide hydroxamic acid (SAHA). Journal of Biological Chemistry, 278, 12579-1258. doi:10.1074/jbc.M213093200

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