| Abstract: |
Histone deacetylase inhibitors (HDACi) can elicit a range of biological responses that affect tumor growth and survival, including inhibition of cell cycle progression, induction of tumor cell-selective apoptosis, suppression of angiogenesis, and modulation of immune responses, and show promising activity against hematological malignancies in clinical trials. Using the Eμ-myc model of B cell lymphoma, we screened tumors with defined genetic alterations in apoptotic pathways for therapeutic responsiveness to the HDACi vorinostat. We demonstrated a direct correlation between induction of tumor cell apoptosis in vivo and therapeutic efficacy. Vorinostat did not require p53 activity or a functional death receptor pathway to kill Eμ-myc lymphomas and mediate a therapeutic response but depended on activation of the intrinsic apoptotic pathway with the proapoptotic BH3-only proteins Bid and Bim playing an important role. Our studies provide important information regarding the mechanisms of action of HDACi that have broad implications regarding stratification of patients receiving HDACi therapy alone or in combination with other anticancer agents. © 2007 by The National Academy of Sciences of the USA. |
| Keywords: |
cancer chemotherapy; controlled study; treatment outcome; survival rate; unclassified drug; oncoprotein; human cell; proto-oncogene proteins; histone deacetylase inhibitor; nonhuman; mouse; animal; animals; mice; animal tissue; cell death; dna damage; cell cycle; protein bcl 2; apoptosis; enzyme inhibition; multiple cycle treatment; etoposide; animal experiment; animal model; bim protein; apoptosis regulatory proteins; membrane proteins; antineoplastic activity; drug effect; enzyme inhibitor; bcl-x protein; angiogenesis; protein p53; mice, inbred c57bl; physiology; c57bl mouse; b cell lymphoma; lymphoma, b-cell; drug antagonism; enzyme inhibitors; histone; lymphoma cell; genes, myc; tumor necrosis factor related apoptosis inducing ligand; membrane protein; lymphoma; tumor cell; vorinostat; hydroxamic acids; tumor suppressor protein p53; kaplan meier method; bh3 interacting domain death agonist protein; histone deacetylases; proto-oncogene proteins c-bcl-2; hydroxamic acid; oncogene myc; apoptosis regulatory protein; histone deacetylase; depsipeptide; spleen cell; tnf-related apoptosis-inducing ligand; protein bid; tnfsf10 protein, mouse; bh3 protein; bh3-only proteins; bid; bim; oxamflatin; bcl 2 binding protein, bim; bcl-2-binding protein, bim; bcl2l1 protein, mouse; bid protein, mouse; protein bcl x
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