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rdf:type |
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lifeskim:mentions |
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pubmed:issue |
10
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pubmed:dateCreated |
2007-5-7
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pubmed:abstractText |
Mantle cell lymphoma (MCL) is an aggressive B-cell lymphoma resistant to conventional chemotherapy. The Bcl-2 pathway is deregulated in these tumors and may represent an interesting target for new therapeutic strategies. The new small-molecule pan-Bcl-2 inhibitor GX15-070 mimics BH3-only proteins by binding to multiple antiapoptotic Bcl-2 members. Here we show that GX15-070 induced apoptosis in vitro in MCL cell lines and primary cells from patients with MCL by releasing Bak from Mcl-1 and Bcl-X(L) at short incubation times and low micromolar doses. GX15-070 was effective in cells bearing defective DNA damage-sensor genes or cell-cycle regulators, inducing Bax and Bak conformational changes, mitochondrial depolarization, phosphatidylserine exposure, and caspase-3 activation. Furthermore, GX15-070 synergized with bortezomib, sensitizing MCL cells to low doses of this proteasome inhibitor, by neutralizing bortezomib-induced Mcl-1 accumulation and cooperating with Noxa to induce Bak displacement from this protein. These events led to an increased activation of the mitochondrial apoptotic pathway. Importantly, GX15-070 alone or in combination with bortezomib showed no significant cytotoxic effect in peripheral blood mononuclear cells from healthy donors. All these findings suggest that GX15-070 alone or in combination with bortezomib represents a new attractive therapeutic approach for MCL treatment.
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pubmed:language |
eng
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pubmed:journal |
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pubmed:citationSubset |
AIM
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pubmed:chemical |
http://linkedlifedata.com/resource/pubmed/chemical/Antineoplastic Agents,
http://linkedlifedata.com/resource/pubmed/chemical/BAK1 protein, human,
http://linkedlifedata.com/resource/pubmed/chemical/BCL2L1 protein, human,
http://linkedlifedata.com/resource/pubmed/chemical/Bax protein (53-86),
http://linkedlifedata.com/resource/pubmed/chemical/Boronic Acids,
http://linkedlifedata.com/resource/pubmed/chemical/Neoplasm Proteins,
http://linkedlifedata.com/resource/pubmed/chemical/PMAIP1 protein, human,
http://linkedlifedata.com/resource/pubmed/chemical/Peptide Fragments,
http://linkedlifedata.com/resource/pubmed/chemical/Proto-Oncogene Proteins,
http://linkedlifedata.com/resource/pubmed/chemical/Proto-Oncogene Proteins c-bcl-2,
http://linkedlifedata.com/resource/pubmed/chemical/Pyrazines,
http://linkedlifedata.com/resource/pubmed/chemical/Pyrroles,
http://linkedlifedata.com/resource/pubmed/chemical/bcl-2 Homologous Antagonist-Killer...,
http://linkedlifedata.com/resource/pubmed/chemical/bcl-X Protein,
http://linkedlifedata.com/resource/pubmed/chemical/bortezomib,
http://linkedlifedata.com/resource/pubmed/chemical/myeloid cell leukemia sequence 1...,
http://linkedlifedata.com/resource/pubmed/chemical/obatoclax
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pubmed:status |
MEDLINE
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pubmed:month |
May
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pubmed:issn |
0006-4971
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pubmed:author |
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pubmed:issnType |
Print
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pubmed:day |
15
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pubmed:volume |
109
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
4441-9
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pubmed:dateRevised |
2010-11-18
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pubmed:meshHeading |
pubmed-meshheading:17227835-Antineoplastic Agents,
pubmed-meshheading:17227835-Antineoplastic Combined Chemotherapy Protocols,
pubmed-meshheading:17227835-Apoptosis,
pubmed-meshheading:17227835-Boronic Acids,
pubmed-meshheading:17227835-Drug Synergism,
pubmed-meshheading:17227835-Gene Expression Regulation, Neoplastic,
pubmed-meshheading:17227835-Humans,
pubmed-meshheading:17227835-Lymphoma, Mantle-Cell,
pubmed-meshheading:17227835-Molecular Mimicry,
pubmed-meshheading:17227835-Neoplasm Proteins,
pubmed-meshheading:17227835-Peptide Fragments,
pubmed-meshheading:17227835-Protein Binding,
pubmed-meshheading:17227835-Proto-Oncogene Proteins,
pubmed-meshheading:17227835-Proto-Oncogene Proteins c-bcl-2,
pubmed-meshheading:17227835-Pyrazines,
pubmed-meshheading:17227835-Pyrroles,
pubmed-meshheading:17227835-Tumor Cells, Cultured,
pubmed-meshheading:17227835-bcl-2 Homologous Antagonist-Killer Protein,
pubmed-meshheading:17227835-bcl-X Protein
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pubmed:year |
2007
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pubmed:articleTitle |
The BH3-mimetic GX15-070 synergizes with bortezomib in mantle cell lymphoma by enhancing Noxa-mediated activation of Bak.
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pubmed:affiliation |
Hematopathology Unit, Department of Pathology, Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer, University of Barcelona, Spain.
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pubmed:publicationType |
Journal Article,
Research Support, Non-U.S. Gov't,
Evaluation Studies
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