|
rdf:type |
|
|
lifeskim:mentions |
|
|
pubmed:issue |
9
|
|
pubmed:dateCreated |
2009-2-27
|
|
pubmed:abstractText |
The apoptotic and therapeutic activities of the histone deacetylase inhibitor (HDACi) vorinostat are blocked by overexpression of Bcl-2 or Bcl-X(L). Herein, we used the small molecule inhibitor ABT-737 to restore sensitivity of Emu-myc lymphomas overexpressing Bcl-2 or Bcl-X(L) to vorinostat and valproic acid (VPA). Combining low-dose ABT-737 with vorinostat or VPA resulted in synergistic apoptosis of these cells. ABT-737 was ineffective against Emu-myc/Mcl-1 and Emu-myc/A1 cells either as a single agent or in combination with HDACi. However, in contrast to the reported binding specificity data, Emu-myc/Bcl-w lymphomas were insensitive to ABT-737 used alone or in combination with HDACi, indicating that the regulatory activity of ABT-737 is restricted to Bcl-2 and Bcl-X(L). Emu-myc lymphomas that expressed Bcl-2 throughout the tumorigenesis process were especially sensitive to ABT-737, while those forced to overexpress Mcl-1 were not. This supports the notion that tumor cells "addicted" to ABT-737 target proteins (ie, Bcl-2 or Bcl-X(L)) are likely to be the most sensitive target cell population. Our studies provide important preclinical data on the binding specificity of ABT-737 and its usefulness against primary hematologic malignancies when used as a single agent and in combination with HDACi.
|
|
pubmed:language |
eng
|
|
pubmed:journal |
|
|
pubmed:citationSubset |
AIM
|
|
pubmed:chemical |
|
|
pubmed:status |
MEDLINE
|
|
pubmed:month |
Feb
|
|
pubmed:issn |
1528-0020
|
|
pubmed:author |
|
|
pubmed:issnType |
Electronic
|
|
pubmed:day |
26
|
|
pubmed:volume |
113
|
|
pubmed:owner |
NLM
|
|
pubmed:authorsComplete |
Y
|
|
pubmed:pagination |
1982-91
|
|
pubmed:dateRevised |
2009-11-19
|
|
pubmed:meshHeading |
pubmed-meshheading:19060243-Animals,
pubmed-meshheading:19060243-Antineoplastic Combined Chemotherapy Protocols,
pubmed-meshheading:19060243-Biphenyl Compounds,
pubmed-meshheading:19060243-Cell Survival,
pubmed-meshheading:19060243-Drug Delivery Systems,
pubmed-meshheading:19060243-Drug Evaluation, Preclinical,
pubmed-meshheading:19060243-Drug Resistance, Neoplasm,
pubmed-meshheading:19060243-Drug Synergism,
pubmed-meshheading:19060243-Enzyme Inhibitors,
pubmed-meshheading:19060243-Genes, bcl-2,
pubmed-meshheading:19060243-Genes, myc,
pubmed-meshheading:19060243-Histone Deacetylase Inhibitors,
pubmed-meshheading:19060243-Hydroxamic Acids,
pubmed-meshheading:19060243-Lymphoma,
pubmed-meshheading:19060243-Mice,
pubmed-meshheading:19060243-Mice, Inbred C57BL,
pubmed-meshheading:19060243-Mice, Transgenic,
pubmed-meshheading:19060243-Nitrophenols,
pubmed-meshheading:19060243-Piperazines,
pubmed-meshheading:19060243-Substrate Specificity,
pubmed-meshheading:19060243-Sulfonamides
|
|
pubmed:year |
2009
|
|
pubmed:articleTitle |
Defining the target specificity of ABT-737 and synergistic antitumor activities in combination with histone deacetylase inhibitors.
|
|
pubmed:affiliation |
Cancer Immunology Program, The Peter MacCallum Cancer Centre, Trescowthick Research Laboratories, East Melbourne, Australia.
|
|
pubmed:publicationType |
Journal Article,
Research Support, Non-U.S. Gov't
|
