Analysis of the apoptotic and therapeutic activities of histone deacetylase inhibitors by using a mouse model of B cell lymphoma.
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 Emu-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 Emu-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.
Lindemann
R K
RK
Cancer Immunology Program, The Peter MacCallum Cancer Institute, Trescowthick Research Laboratories, St. Andrews Place, East Melbourne, Victoria 3002, Australia.
Newbold
A
A
Whitecross
K F
KF
Cluse
L A
LA
Frew
A J
AJ
Ellis
L
L
Williams
S
S
Wiegmans
A P
AP
Dear
A E
AE
Scott
C L
CL
Pellegrini
M
M
Wei
A
A
Richon
V M
VM
Marks
Paul A
PA
Lowe
S W
SW
Smyth
M J
MJ
Johnstone
R W
RW
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D051017:Apoptosis Regulatory Proteins / Q000502:physiology; D051023:BH3 Interacting Domain Death Agonist Protein / Q000502:physiology; D000072224:Bcl-2-Like Protein 11; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D016259:Genes, myc; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids / Q000627:therapeutic use*; D016393:Lymphoma, B-Cell / Q000188:drug therapy*; D008565:Membrane Proteins / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D011518:Proto-Oncogene Proteins / Q000502:physiology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000502:physiology; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000502:physiology; D016159:Tumor Suppressor Protein p53 / Q000502:physiology; D000077337:Vorinostat; D051020:bcl-X Protein / Q000502:physiology
D051017:Apoptosis Regulatory Proteins; D051023:BH3 Interacting Domain Death Agonist Protein; D000072224:Bcl-2-Like Protein 11; C494812:Bcl2l1 protein, mouse; C000606776:Bcl2l11 protein, mouse; C494815:Bid protein, mouse; D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D008565:Membrane Proteins; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D053221:TNF-Related Apoptosis-Inducing Ligand; C505654:Tnfsf10 protein, mouse; D016159:Tumor Suppressor Protein p53; D051020:bcl-X Protein; D000077337:Vorinostat