title: Susceptibility of multidrug resistance tumor cells to apoptosis induction by histone deacetylase inhibitors.
abstract: The main goal of our study has been to analyze the efficiency of new anticancer drugs, specifically histone deacetylase inhibitors, in tumor cells bearing a multidrug resistance phenotype. We report that the histone deacetylase inhibitors, Trichostatin A and Suberoylanilide Hydroxamic Acid (SAHA), dramatically reduce cell viability and promote apoptosis in different drug-resistant cells, affecting in a much lesser extent to their parental drug-sensitive counterparts. The differential effects induced by Trichostatin A and SAHA between drug-sensitive and drug-resistant cells are reflected on the main characteristics of the resistant phenotype. Thus, reverse transcription-PCR and Western immunoblots confirm that both histone deacetylase inhibitors promote endogenous down-regulation of P-glycoprotein, which is overexpressed in the drug-resistant cells. Transfection of drug-sensitive cells with the P-glycoprotein cDNA ruled out the a priori possible association between apoptosis and down-regulation of P-glycoprotein induced by the histone deacetylase inhibitors. The results suggest a therapeutic potential of histone deacetylase inhibitors in the treatment of cancers with acquired resistance.
authors.affiliation: Centro de Biologia Molecular y Celular, Universidad Miguel Hernandez, Elche (Alicante), Spain.
authors.forename: Maria D
authors.initials: MD
authors.lastname: Castro-Galache
authors.forename: Jose A
authors.initials: JA
authors.lastname: Ferragut
authors.forename: Victor M
authors.initials: VM
authors.lastname: Barbera
authors.forename: Elena
authors.initials: E
authors.lastname: Martín-Orozco
authors.forename: Jose M
authors.initials: JM
authors.lastname: Gonzalez-Ros
authors.forename: Pilar
authors.initials: P
authors.lastname: Garcia-Morales
authors.forename: Miguel
authors.initials: M
authors.lastname: Saceda
mesh_terms: D000107:Acetylation; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D002455:Cell Division / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D056572:Histone Deacetylase Inhibitors; D006657:Histones / Q000378:metabolism; D006877:Hydroxamic Acids / Q000494:pharmacology*; D051379:Mice; D014162:Transfection; D014407:Tumor Cells, Cultured; D000077337:Vorinostat
chemical_list: D000970:Antineoplastic Agents; D056572:Histone Deacetylase Inhibitors; D006657:Histones; D006877:Hydroxamic Acids; C012589:trichostatin A; D000077337:Vorinostat