Source:http://linkedlifedata.com/resource/pubmed/id/17130834
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| Predicate | Object |
|---|---|
| rdf:type | |
| lifeskim:mentions | |
| pubmed:issue |
21
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| pubmed:dateCreated |
2007-5-14
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| pubmed:abstractText |
Although the BCR/ABL tyrosine kinase inhibitor imatinib is highly effective for treatment of chronic myeloid leukemia (CML) and Philadelphia-chromosome positive acute lymphoblastic leukemia (ALL), relapse with emerging imatinib-resistance mutations in the BCR/ABL kinase domain poses a significant problem. Here, we demonstrate that rottlerin, a putative protein kinase C-delta (PKCdelta)-specific inhibitor, acts synergistically with imatinib to induce apoptosis of BCR/ABL-expressing K562 and Ton.B210 cells. However, rottlerin inhibited neither PKCdelta nor BCR/ABL in these cells. On the other hand, rottlerin, previously characterized also as a mitochondrial uncoupler, transiently but significantly reduced mitochondrial membrane potential and gradually induced mitochondrial membrane permeabilization. Moreover, two other mitochondrial uncouplers, FCCP and DNP, very similarly induced apoptosis of BCR/ABL-expressing cells in a synergistic manner with imatinib. Imatinib synergistically enhanced mitochondrial membrane permeabilization induced by mitochondrial uncouplers, which led to release of cytochrome c into the cytoplasm and activation of caspases-3 and -9. Rottlerin also enhanced the cytotoxic effect of imatinib in leukemic cells from patients with CML blast crisis and Ph-positive ALL or a cell line expressing the imatinib-resistant E255K BCR/ABL mutant. The present study indicates that rottlerin synergistically enhances imatinib-induced apoptosis through its mitochondrial uncoupling effect independent of PKCdelta and may contribute to the development of new treatment strategy to overcome the imatinib resistance and to cure the BCR/ABL expressing leukemias.
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| pubmed:language |
eng
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| pubmed:journal | |
| pubmed:citationSubset |
IM
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| pubmed:chemical |
http://linkedlifedata.com/resource/pubmed/chemical/Acetophenones,
http://linkedlifedata.com/resource/pubmed/chemical/Antineoplastic Agents,
http://linkedlifedata.com/resource/pubmed/chemical/Bcr-Abl tyrosine kinase,
http://linkedlifedata.com/resource/pubmed/chemical/Benzopyrans,
http://linkedlifedata.com/resource/pubmed/chemical/Fusion Proteins, bcr-abl,
http://linkedlifedata.com/resource/pubmed/chemical/Piperazines,
http://linkedlifedata.com/resource/pubmed/chemical/Protein Kinase C-delta,
http://linkedlifedata.com/resource/pubmed/chemical/Protein Kinase Inhibitors,
http://linkedlifedata.com/resource/pubmed/chemical/Protein-Tyrosine Kinases,
http://linkedlifedata.com/resource/pubmed/chemical/Pyrimidines,
http://linkedlifedata.com/resource/pubmed/chemical/Uncoupling Agents,
http://linkedlifedata.com/resource/pubmed/chemical/imatinib,
http://linkedlifedata.com/resource/pubmed/chemical/rottlerin
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| pubmed:status |
MEDLINE
|
| pubmed:month |
May
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| pubmed:issn |
0950-9232
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| pubmed:author | |
| pubmed:issnType |
Print
|
| pubmed:day |
10
|
| pubmed:volume |
26
|
| pubmed:owner |
NLM
|
| pubmed:authorsComplete |
Y
|
| pubmed:pagination |
2975-87
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| pubmed:dateRevised |
2009-11-19
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| pubmed:meshHeading |
pubmed-meshheading:17130834-Acetophenones,
pubmed-meshheading:17130834-Animals,
pubmed-meshheading:17130834-Antineoplastic Agents,
pubmed-meshheading:17130834-Apoptosis,
pubmed-meshheading:17130834-Benzopyrans,
pubmed-meshheading:17130834-Drug Synergism,
pubmed-meshheading:17130834-Fusion Proteins, bcr-abl,
pubmed-meshheading:17130834-Humans,
pubmed-meshheading:17130834-K562 Cells,
pubmed-meshheading:17130834-Leukemia, Erythroblastic, Acute,
pubmed-meshheading:17130834-Mice,
pubmed-meshheading:17130834-Mitochondria,
pubmed-meshheading:17130834-Piperazines,
pubmed-meshheading:17130834-Protein Kinase C-delta,
pubmed-meshheading:17130834-Protein Kinase Inhibitors,
pubmed-meshheading:17130834-Protein-Tyrosine Kinases,
pubmed-meshheading:17130834-Pyrimidines,
pubmed-meshheading:17130834-Uncoupling Agents,
pubmed-meshheading:17130834-Up-Regulation
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| pubmed:year |
2007
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| pubmed:articleTitle |
Rottlerin synergistically enhances imatinib-induced apoptosis of BCR/ABL-expressing cells through its mitochondrial uncoupling effect independent of protein kinase C-delta.
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| pubmed:affiliation |
Department of Hematology, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo, Japan.
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| pubmed:publicationType |
Journal Article,
Research Support, Non-U.S. Gov't
|