title: Histone deacetylase inhibitors promote apoptosis and senescence in human mesenchymal stem cells.
abstract: Histone deacetylase inhibitors (HDACi) have received a great amount of attention for their antitumoral properties. Suberoyl anilide hydroxamic acid (SAHA) and MS-275 are among the more promising HDACi for cancer treatments. Although these HDACi compounds exert low toxicity on normal cells, the therapies based on these molecules can cause side effects that can greatly impair the functions of the bone marrow microenvironment. This is a complex system that contains several types of stem cells, such as mesenchymal stem cells (MSCs). We conducted comparative studies on the effects of SAHA and MS-275 on human MSCs in order to ascertain if these compounds can impair the physiology of MSCs. Both SAHA and MS-275 induced an arrest in the cell cycle along with the induction of apoptotic pathways as evidenced by flow cytometry, annexin assay, detection of activated caspase 9, and molecular analysis of Bax/Bcl-2 expression. The MS-275 treatment induced an increase of senescent cells, whereas in cells treated with SAHA, we detected a reduction of senescent cells compared to the control. We hypothesize that SAHA preferentially transactivates apoptotic genes, thereby inducing a great majority of the damaged cells to die by programmed cell death rather than senescence. Following the HDACi treatment, we observed a decrease in the expression of some genes that are involved in the regulation of stem cell properties. This suggests that SAHA and MS-275 could also be involved in the impairment of the stemness characteristics of MSCs. The phenomena that were induced by HDACi treatment were associated with an upregulation of several cyclin kinase inhibitors. By contrast, the p53-p21 pathway is apparently not involved in these processes.
authors.affiliation: Department of Experimental Medicine, Section of Biotechnology and Molecular Biology, Excellence Research Center for Cardiovascular Diseases, Second University of Naples, Naples, Italy.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Di Bernardo
authors.forename: Tiziana
authors.initials: T
authors.lastname: Squillaro
authors.forename: Carmela
authors.initials: C
authors.lastname: Dell'Aversana
authors.forename: Marco
authors.initials: M
authors.lastname: Miceli
authors.forename: Marilena
authors.initials: M
authors.lastname: Cipollaro
authors.forename: Antonino
authors.initials: A
authors.lastname: Cascino
authors.forename: Lucia
authors.initials: L
authors.lastname: Altucci
authors.forename: Umberto
authors.initials: U
authors.lastname: Galderisi
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D001549:Benzamides / Q000494:pharmacology / Q000627:therapeutic use; D002453:Cell Cycle / Q000187:drug effects / Q000502:physiology; D016922:Cellular Senescence / Q000187:drug effects*; D004791:Enzyme Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D056572:Histone Deacetylase Inhibitors; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology / Q000627:therapeutic use; D059630:Mesenchymal Stem Cells / Q000187:drug effects / Q000502:physiology; D009369:Neoplasms / Q000188:drug therapy; D011725:Pyridines / Q000494:pharmacology / Q000627:therapeutic use; D000077337:Vorinostat
chemical_list: D001549:Benzamides; D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D011725:Pyridines; C118739:entinostat; D000077337:Vorinostat