title: Do iron chelators increase the antiproliferative effect of trichostatin A through a glucose-regulated protein 78 mediated mechanism?
abstract: Histone deacetylase (HDAC) inhibitors, such as trichostatin A (TSA), and iron chelators, including deferoxamine (DFO) and phenanthroline (PHEN), appear to have anticancer effects. We hypothesized that the HDAC inhibitors and iron chelators would be synergistic with their effect on breast cancer cell line MCF7, because the HDAC inhibitors increase glucose-regulated protein 78 (Grp78) and the iron chelators reduce its expression. Although the administration of TSA alone resulted in a dose-related decrease in the cell index, it did not have an antiproliferative effect except the 62.5 and 500 nM of TSA. However, all doses of TSA produced a cytotoxic effect from the initial hours when combined with 150 μM of DFO and 25 μM of PHEN. DFO and PHEN downregulated Grp78, Grp94, and MRP1 expressions and upregulated CHOP and HO-1 expressions. TSA upregulated all the genes in various rates when used alone but resulted in decreased expression levels when combined with DFO and PHEN. Increased HDAC-1 levels in the Grp78 promoter region indicated that DFO and PHEN either promoted binding of HDAC-1 to this region or inhibited its detachment. We determined that the reduction of increased Grp78, Grp94, HO-1, and MRP1 expressions, which appears to inhibit the chemotherapeutic effect of TSA, through the combination with DFO or PHEN will contribute to the anticancer effect.
authors.affiliation: Public Health Laboratory, 55139, Kurupelit, Trabzon, Turkey.
authors.forename: Veli
authors.initials: V
authors.lastname: Kilinc
authors.forename: Abdulkerim
authors.initials: A
authors.lastname: Bedir
authors.forename: Ali
authors.initials: A
authors.lastname: Okuyucu
authors.forename: Osman
authors.initials: O
authors.lastname: Salis
authors.forename: Hasan
authors.initials: H
authors.lastname: Alacam
authors.forename: Sedat
authors.initials: S
authors.lastname: Gulten
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D000091342:Endoplasmic Reticulum Chaperone BiP; D006360:Heat-Shock Proteins / Q000235:genetics / Q000502:physiology*; D051547:Heme Oxygenase-1 / Q000235:genetics; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology*; D007502:Iron Chelating Agents / Q000494:pharmacology*; D061986:MCF-7 Cells; D008562:Membrane Glycoproteins / Q000502:physiology; D011401:Promoter Regions, Genetic; D051742:Transcription Factor CHOP / Q000235:genetics
chemical_list: D000970:Antineoplastic Agents; C497249:DDIT3 protein, human; D000091342:Endoplasmic Reticulum Chaperone BiP; C000717247:HSPA5 protein, human; D006360:Heat-Shock Proteins; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D007502:Iron Chelating Agents; D008562:Membrane Glycoproteins; C053387:endoplasmin; D051742:Transcription Factor CHOP; C012589:trichostatin A; C496541:HMOX1 protein, human; D051547:Heme Oxygenase-1