title: The synergistic effect of SAHA and parthenolide in MDA-MB231 breast cancer cells.
abstract: The sesquiterpene lactone Parthenolide (PN) exerted a cytotoxic effect on MDA-MB231 cells, a triple-negative breast cancer (TNBC) cell line, but its effectiveness was scarce when employed at low doses. This represents an obstacle for a therapeutic utilization of PN. In order to overcome this difficulty we associated to PN the suberoylanilide hydroxamic acid (SAHA), an histone deacetylase inhibitor. Our results show that SAHA synergistically sensitized MDA-MB231 cells to the cytotoxic effect of PN. It is noteworthy that treatment with PN alone stimulated the survival pathway Akt/mTOR and the consequent nuclear translocation of Nrf2, while treatment with SAHA alone induced autophagic activity. However, when the cells were treated with SAHA/PN combination, SAHA suppressed PN effect on Akt/mTOR/Nrf2 pathway, while PN reduced the prosurvival autophagic activity of SAHA. In addition SAHA/PN combination induced GSH depletion, fall in Δψm, release of cytochrome c, activation of caspase 3 and apoptosis. Finally we demonstrated that combined treatment maintained both hyperacetylation of histones H3 and H4 induced by SAHA and down-regulation of DNMT1 expression induced by PN. Inhibition of the DNA-binding activity of NF-kB, which is determined by PN, was also observed after combined treatment. In conclusion, combination of PN to SAHA inhibits the cytoprotective responses induced by the single compounds, but does not alter the mechanisms leading to the cytotoxic effects. Taken together our results suggest that this combination could be a candidate for TNBC therapy.
authors.affiliation: Department of Experimental Biomedicine and Clinical Neurosciences (BioNeC), Laboratory of Biochemistry, Polyclinic, University of Palermo, Palermo, Italy.
authors.forename: Daniela
authors.initials: D
authors.lastname: Carlisi
authors.forename: Marianna
authors.initials: M
authors.lastname: Lauricella
authors.forename: Antonella
authors.initials: A
authors.lastname: D'Anneo
authors.forename: Giuseppina
authors.initials: G
authors.lastname: Buttitta
authors.forename: Sonia
authors.initials: S
authors.lastname: Emanuele
authors.forename: Riccardo
authors.initials: R
authors.lastname: di Fiore
authors.forename: Roberta
authors.initials: R
authors.lastname: Martinez
authors.forename: Christian
authors.initials: C
authors.lastname: Rolfo
authors.forename: Renza
authors.initials: R
authors.lastname: Vento
authors.forename: Giovanni
authors.initials: G
authors.lastname: Tesoriere
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D001343:Autophagy / Q000187:drug effects; D001943:Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism; D045744:Cell Line, Tumor / Q000187:drug effects*; D015536:Down-Regulation / Q000187:drug effects; D004357:Drug Synergism; D005260:Female; D056572:Histone Deacetylase Inhibitors / Q000378:metabolism; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology*; D016328:NF-kappa B / Q000378:metabolism; D012717:Sesquiterpenes / Q000494:pharmacology*; D000077337:Vorinostat
chemical_list: D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D016328:NF-kappa B; D012717:Sesquiterpenes; C002669:parthenolide; D000077337:Vorinostat