Analysis of the apoptotic and therapeutic activities of histone deacetylase inhibitors by using a mouse model of B cell lymphoma

Lindemann, RK; Newbold, A; Whitecross, KF; Cluse, LA; Frew, AJ; Ellis, L; Williams, S; Wiegmans, AP; Dear, AE; Scott, CL; Pellegrini, M; Wei, A; Richon, VM; Marks, PA; Lowe, SW; Smyth, MJ; Johnstone, RW

Author(s): Lindemann, RK; Newbold, A; Whitecross, KF; Cluse, LA; Frew, AJ; Ellis, L; Williams, S; Wiegmans, AP; Dear, AE; Scott, CL; Pellegrini, M; Wei, A; Richon, VM; Marks, PA; Lowe, SW; Smyth, MJ; Johnstone, RW;
Details: Publication Year 2007-05-08,Volume 104,Issue #19,Page 8071-8076
Journal Title: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Publication Type: Journal Article
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 E mu-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 E mu-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.
Publisher: NATL ACAD SCIENCES
Keywords: SUBEROYLANILIDE HYDROXAMIC ACID; HDAC INHIBITORS; GASTRIC-CANCER; LEUKEMIA-CELLS; ACTIVATION; DEATH; P53; INDUCTION; PATHWAY; SAHA
Publisher's Version: https://doi.org/10.1073/pnas.0702294104
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2007-05-08 12:00:00