title: Vorinostat induced cellular stress disrupts the p38 mitogen activated protein kinase and extracellular signal regulated kinase pathways leading to apoptosis in Waldenström macroglobulinemia cells.
abstract: Histone deacetylases (HDACs) are aberrantly expressed, and inhibitors of HDACs induce apoptosis in lymphoplasmacytic cells (LPCs) in Waldenström macroglobulinemia (WM). The molecular profile by which these agents induce apoptosis in WM LPCs remains to be delineated. We examined the activity of the histone deacetylase inhibitor, vorinostat, and dissected its pro-apoptotic pathways in WM LPCs. Vorinostat induced apoptosis in WM cells through activating specific caspases at varying times. Inhibitors of apoptosis (IAPs) were down-regulated after vorinostat treatment. Cellular stress induced in vorinostat-treated WM cells was reflected by changes in the mitogen activated protein kinase (MAPK) pathways. Activated phospho-p38 MAPK was up-regulated at 12 h, while phospho-extracellular signal-regulated kinase (Erk) abruptly decreased at 24 h. Bortezomib did not augment vorinostat induced primary WM cell killing as reported in other B-cell disorders. These studies support that stress induced apoptosis in vorinostat-treated WM LPCs is mediated through disrupting the activity of the Erk and p38 MAPK pathways.
authors.affiliation: Bing Center for Waldenström's Macroglobulinemia, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
authors.forename: Jenny Y
authors.initials: JY
authors.lastname: Sun
authors.forename: Hsiuyi
authors.initials: H
authors.lastname: Tseng
authors.forename: Lian
authors.initials: L
authors.lastname: Xu
authors.forename: Zachary
authors.initials: Z
authors.lastname: Hunter
authors.forename: Bryan
authors.initials: B
authors.lastname: Ciccarelli
authors.forename: Mariateresa
authors.initials: M
authors.lastname: Fulciniti
authors.forename: Bangmin
authors.initials: B
authors.lastname: Zhu
authors.forename: Kaveh
authors.initials: K
authors.lastname: Maghsoudi
authors.forename: Guang
authors.initials: G
authors.lastname: Yang
authors.forename: Ping
authors.initials: P
authors.lastname: Gong
authors.forename: Yangsheng
authors.initials: Y
authors.lastname: Zhou
authors.forename: Xia
authors.initials: X
authors.lastname: Liu
authors.forename: Nikhil C
authors.initials: NC
authors.lastname: Munshi
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Patterson
authors.forename: Steven P
authors.initials: SP
authors.lastname: Treon
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D001897:Boronic Acids / Q000494:pharmacology / Q000633:toxicity; D000069286:Bortezomib; D020169:Caspases / Q000378:metabolism; D002460:Cell Line; D004789:Enzyme Activation / Q000187:drug effects; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology* / Q000633:toxicity; D006655:Histone Deacetylases / Q000378:metabolism; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology* / Q000633:toxicity; D011719:Pyrazines / Q000494:pharmacology / Q000633:toxicity; D013312:Stress, Physiological / Q000187:drug effects*; D000077337:Vorinostat; D008258:Waldenstrom Macroglobulinemia / Q000201:enzymology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
chemical_list: D001897:Boronic Acids; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D011719:Pyrazines; D000077337:Vorinostat; D000069286:Bortezomib; D048049:Extracellular Signal-Regulated MAP Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D020169:Caspases; D006655:Histone Deacetylases