Document Detail


A novel Bcl-2/Bcl-X(L)/Bcl-w inhibitor ABT-737 as therapy in multiple myeloma.
MedLine Citation:
PMID:  17016430     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Bcl-2 or Bcl-X(L) confers resistance to chemotherapy in multiple myeloma (MM). Here we characterized the effects of ABT-737, a potent small-molecule inhibitor of antiapoptotic proteins Bcl-2, Bcl-X(L) and Bcl-w with markedly higher affinity than previously reported compounds, on human MM cells. ABT-737 induces apoptosis in MM cells, including those resistant to conventional therapy. Examination of purified patient MM cells demonstrated similar results, without significant toxicity against normal peripheral blood mononuclear cells and MM bone marrow stromal cells. Importantly, ABT-737 decreases the viability of bortezomib-, dexamethasone-(Dex) and thalidomide-refractory patient MM cells. Additionally, ABT-737 abrogates MM cell growth triggered by interleukin-6 or insulin-like growth factor-1. Mechanistic studies show that ABT-737-induced apoptosis is associated with activation of caspase-8, caspase-9 and caspase-3, followed by poly(ADP-ribose) polymerase cleavage. Combining ABT-737 with proteasome inhibitor bortezomib, melphalan or dexamethasone induces additive anti-MM activity. Taken together, our study provides the rationale for clinical protocols evaluating ABT-737, alone and together with botezomib, mephalan or dexamethasone, to enhance MM cell killing, overcome drug resistance conferred by Bcl-2 and improve patient outcome in MM.
Authors:
D Chauhan; M Velankar; M Brahmandam; T Hideshima; K Podar; P Richardson; R Schlossman; I Ghobrial; N Raje; N Munshi; K C Anderson
Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2006-10-02
Journal Detail:
Title:  Oncogene     Volume:  26     ISSN:  0950-9232     ISO Abbreviation:  Oncogene     Publication Date:  2007 Apr 
Date Detail:
Created Date:  2007-04-05     Completed Date:  2007-09-17     Revised Date:  2007-12-03    
Medline Journal Info:
Nlm Unique ID:  8711562     Medline TA:  Oncogene     Country:  England    
Other Details:
Languages:  eng     Pagination:  2374-80     Citation Subset:  IM    
Affiliation:
The Jerome Lipper Multiple Myeloma Center, Department of Medical Oncology, Dana Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA.
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MeSH Terms
Descriptor/Qualifier:
Antineoplastic Agents / pharmacology*,  toxicity
Apoptosis Regulatory Proteins / antagonists & inhibitors*
Biphenyl Compounds / pharmacology*
Bone Marrow Cells / drug effects
Boronic Acids / toxicity
Cell Division / drug effects
Cell Survival / drug effects
Humans
Multiple Myeloma / drug therapy*,  pathology
Nitrophenols / pharmacology*
Piperazines / pharmacology
Proto-Oncogene Proteins c-bcl-2 / antagonists & inhibitors*
Pyrazines / toxicity
Sulfonamides / pharmacology*
Tumor Cells, Cultured
bcl-X Protein / antagonists & inhibitors*
Grant Support
ID/Acronym/Agency:
IP50CA10070/CA/NCI NIH HHS; P0-1 CA 78373/CA/NCI NIH HHS; R0-1 CA50947/CA/NCI NIH HHS
Chemical
Reg. No./Substance:
0/ABT-737; 0/Antineoplastic Agents; 0/Apoptosis Regulatory Proteins; 0/BCL2L2 protein, human; 0/Biphenyl Compounds; 0/Boronic Acids; 0/Nitrophenols; 0/Piperazines; 0/Proto-Oncogene Proteins c-bcl-2; 0/Pyrazines; 0/Sulfonamides; 0/bcl-X Protein; 0/bortezomib

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