J Cancer 2017; 8(1):19-28. doi:10.7150/jca.16655

Research Paper

Histone Deacetylase Inhibitor SAHA as Potential Targeted Therapy Agent for Larynx Cancer Cells

Aneta Grabarska1✉, Jarogniew J. Łuszczki2,3, Ewa Nowosadzka1, Ewelina Gumbarewicz1, Witold Jeleniewicz1, Magdalena Dmoszyńska-Graniczka1, Krystyna Kowalczuk1, Krzysztof Kupisz5, Krzysztof Polberg4, Andrzej Stepulak1,4

1. Department of Biochemistry and Molecular Biology, Medical University of Lublin, Poland.
2. Department of Pathophysiology, Medical University of Lublin, Lublin, Poland.
3. Isobolographic Analysis Laboratory, Institute of Rural Health, Lublin, Poland.
4. Department of Otolaryngology, MSWiA Hospital, Poland.
5. Department of Otolaryngology and Head and Neck Surgery, Specialist District Hospital, Lublin, Poland.

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Grabarska A, Łuszczki JJ, Nowosadzka E, Gumbarewicz E, Jeleniewicz W, Dmoszyńska-Graniczka M, Kowalczuk K, Kupisz K, Polberg K, Stepulak A. Histone Deacetylase Inhibitor SAHA as Potential Targeted Therapy Agent for Larynx Cancer Cells. J Cancer 2017; 8(1):19-28. doi:10.7150/jca.16655. Available from http://www.jcancer.org/v08p0019.htm

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Objective: Laryngeal squamous cell carcinoma is one of the most common malignant tumors in the head and neck region. Due to the poor response to chemotherapeutics in patients and low survival rate, successful treatment of larynx cancer still remains a challenge. Therefore, the identification of novel treatment options is needed. We investigated the anticancer effects of suberoylanilide hydroxamic acid (SAHA), a histone deacetylase inhibitor, on two different laryngeal cancer cell lines RK33 and RK45. We also studied the antiproliferative action of SAHA in combination with cisplatin and defined the type of pharmacological interaction between these drugs. Materials and Methods: Viability and proliferation of larynx cancer cell lines were studied by methylthiazolyldiphenyl-tetrazolium bromide method and 5-bromo-2-deoxyuridine incorporation assay, respectively. The type of interaction between SAHA and cisplatin was determined by an isobolographic analysis. Western blotting, flow cytometry and quantitative polymerase chain reaction method were used to determine acetylation of histone H3, cell cycle progression and genes expression, respectively. Apoptosis was assessed by means of nucleosomes released to cytosol. Results: SAHA alone or in combination with cisplatin inhibited larynx cancer cells proliferation, whereas displayed relatively low toxicity against normal cells - primary cultures of human skin fibroblasts. The mixture of SAHA with cisplatin exerted additive and synergistic interaction in RK33 and RK45 cells, respectively. We showed that SAHA induced hyperacetylation of histone H3 K9, K14 and K23 and triggered apoptosis. SAHA also caused cell cycle arrest by upregulation of CDKN1A and downregulation of CCND1 encoding p21WAF1/CIP1 and cyclin D1 proteins, respectively. Conclusion: Our studies demonstrated that SAHA may be considered as a potential therapeutic agent against larynx tumors.

Keywords: larynx cancer, histone deacetylase inhibitors, suberoylanilide hydroxamic acid (SAHA), cisplatin (CDDP), isobolography.