title: Assessment of Interactions between Cisplatin and Two Histone Deacetylase Inhibitors in MCF7, T47D and MDA-MB-231 Human Breast Cancer Cell Lines - An Isobolographic Analysis.
abstract: Histone deacetylase inhibitors (HDIs) are promising anticancer drugs, which inhibit proliferation of a wide variety of cancer cells including breast carcinoma cells. In the present study, we investigated the influence of valproic acid (VPA) and suberoylanilide hydroxamic acid (SAHA, vorinostat), alone or in combination with cisplatin (CDDP) on proliferation, induction of apoptosis and cell cycle progression in MCF7, T47D and MDA-MB-231 human breast carcinoma cell lines. The type of interaction between HDIs and CDDP was determined by an isobolographic analysis. The isobolographic analysis is a very precise and rigorous pharmacodynamic method, to determine the presence of synergism, addition or antagonism between different drugs with using variety of fixed dose ratios. Our experiments show that the combinations of CDDP with SAHA or VPA at a fixed-ratio of 1:1 exerted additive interaction in the viability of MCF7 cells, while in T47D cells there was a tendency to synergy. In contrast, sub-additive (antagonistic) interaction was observed for the combination of CDDP with VPA in MDA-MB-231 "triple-negative" (i.e. estrogen receptor negative, progesterone receptor negative, and HER-2 negative) human breast cancer cells, whereas combination of CDDP with SAHA in the same MDA-MB-231 cell line yielded additive interaction. Additionally, combined HDIs/CDDP treatment resulted in increase in apoptosis and cell cycle arrest in all tested breast cancer cell lines in comparison with a single therapy. In conclusion, the additive interaction of CDDP with SAHA or VPA suggests that HDIs could be combined with CDDP in order to optimize treatment regimen in some human breast cancers.
authors.affiliation: Department of Biochemistry and Molecular Biology, Medical University of Lublin, Lublin, Poland.
authors.forename: Anna
authors.initials: A
authors.lastname: Wawruszak
authors.affiliation: Department of Pathophysiology, Medical University of Lublin, Lublin, Poland.|Isobolographic Analysis Laboratory, Institute of Rural Health, Lublin, Poland.
authors.forename: Jarogniew J
authors.initials: JJ
authors.lastname: Luszczki
authors.affiliation: Department of Biochemistry and Molecular Biology, Medical University of Lublin, Lublin, Poland.
authors.forename: Aneta
authors.initials: A
authors.lastname: Grabarska
authors.affiliation: Department of Biochemistry and Molecular Biology, Medical University of Lublin, Lublin, Poland.
authors.forename: Ewelina
authors.initials: E
authors.lastname: Gumbarewicz
authors.affiliation: Department of Biochemistry and Molecular Biology, Medical University of Lublin, Lublin, Poland.
authors.forename: Magdalena
authors.initials: M
authors.lastname: Dmoszynska-Graniczka
authors.affiliation: Department of Otolaryngology, MSW Hospital, Lublin, Poland.
authors.forename: Krzysztof
authors.initials: K
authors.lastname: Polberg
authors.affiliation: Department of Biochemistry and Molecular Biology, Medical University of Lublin, Lublin, Poland.|Department of Otolaryngology, MSW Hospital, Lublin, Poland.
authors.forename: Andrzej
authors.initials: A
authors.lastname: Stepulak
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002945:Cisplatin / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D005260:Female; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology*; D020128:Inhibitory Concentration 50; D061986:MCF-7 Cells; D014635:Valproic Acid / Q000494:pharmacology*; D000077337:Vorinostat
chemical_list: D000970:Antineoplastic Agents; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D000077337:Vorinostat; D014635:Valproic Acid; D002945:Cisplatin