LYMPHOID NEOPLASIA Bcl-2, Bcl-xL, and Bcl-w are not equivalent targets of ABT-737 and navitoclax (ABT-263) in lymphoid and leukemic cells
نویسندگان
چکیده
1The Walter and Eliza Hall Institute of Medical Research, Parkville, Australia; 2Department of Medical Biology, University of Melbourne, Melbourne, Australia; 3Faculty of Medicine, Dentistry and Health Sciences, The University of Melbourne, Melbourne, Australia; 4Children’s Cancer Centre, Monash Medical Centre, Clayton, Australia; 5Department of Research Oncology, Genentech, South San Francisco, CA; and 6Department of Clinical Hematology and BMT, The Royal Melbourne Hospital, Parkville, Australia
منابع مشابه
An antiapoptotic BCL-2 family expression index predicts the response of chronic lymphocytic leukemia to ABT-737.
The antiapoptotic BCL-2 proteins regulate lymphocyte survival and are over-expressed in lymphoid malignancies, including chronic lymphocytic leukemia. The small molecule inhibitor ABT-737 binds with high affinity to BCL-2, BCL-XL, and BCL-W but with low affinity to MCL-1, BFL-1, and BCL-B. The active analog of ABT-737, navitoclax, has shown a high therapeutic index in lymphoid malignancies; dev...
متن کاملBrief Report LYMPHOID NEOPLASIA ABT-199, a new Bcl-2–specific BH3 mimetic, has in vivo efficacy against aggressive Myc-driven mouse lymphomas without provoking thrombocytopenia
Whether cells live or die by apoptosis when confronted with diverse stresses, including radiation and chemotherapy, is determined by interactions between opposing factions of the Bcl-2 family of proteins. Bcl-2 prevents apoptosis, as do Bcl-xL, Bcl-w, Mcl-1, and A1, but other close relatives Bax and Bak instead provoke apoptosis. Stress signals induce distant relatives known as BH3-only protein...
متن کاملABT-199, a new Bcl-2-specific BH3 mimetic, has in vivo efficacy against aggressive Myc-driven mouse lymphomas without provoking thrombocytopenia.
BH3-only proteins trigger the stress apoptosis pathway and chemical mimetics have great potential for cancer therapy. BH3-only proteins inhibit antiapoptotic members of the Bcl-2 family. Promising BH3 mimetic ABT-737 and the related orally available compound ABT-263 (navitoclax) bind avidly to antiapoptotic Bcl-2, Bcl-xL, and Bcl-w. However, their interaction with Bcl-xL provokes thrombocytopen...
متن کاملSelective Bcl-2 inhibition to treat chronic lymphocytic leukemia and non-Hodgkin lymphoma.
ABT-199, a second-generation BH3 mimetic, is an orally bioavailable, small molecule inhibitor that selectively targets B-cell lymphoma/leukemia 2 (Bcl-2). Bcl-2 is a key protein that inhibits the intrinsic mitochondrial pathway of apoptosis. First-generation BH3 mimetics such as navitoclax (ABT-263) had a broad range of inhibitory activity against Bcl-2 family members, including Bcl-2, Bcl-XL, ...
متن کاملLYMPHOID NEOPLASIA Defining the target specificity of ABT-737 and synergistic antitumor activities in combination with histone deacetylase inhibitors
The apoptotic and therapeutic activities of the histone deacetylase inhibitor (HDACi) vorinostat are blocked by overexpresssion of Bcl-2 or Bcl-XL. Herein, we used the small molecule inhibitor ABT737 to restore sensitivity of E -myc lymphomas overexpressing Bcl-2 or Bcl-XL to vorinostat and valproic acid (VPA). Combining low-dose ABT-737 with vorinostat or VPA resulted in synergistic apoptosis ...
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