Source:http://linkedlifedata.com/resource/pubmed/id/18951975
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| Predicate | Object |
|---|---|
| rdf:type | |
| lifeskim:mentions | |
| pubmed:issue |
1
|
| pubmed:dateCreated |
2008-12-2
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| pubmed:abstractText |
The antipsychotic drug haloperidol is still used to treat psychosis and "agitation", often with devastating consequences, particularly in geriatric and pre-demented patients. Cytotoxicity induced by haloperidol has been associated with induction of Bcl-XS, a pro-apoptotic member of the Bcl-2 family, as well as with modulation of the Akt pro-survival pathway. Using preneuronal PC12 and primary neuronal cultures, we show that haloperidol inactivates Akt. This induces the dephosphorylation of serine residues in Bcl-XS and promotes its association with the mitochondrial voltage-dependent anion channel (VDAC), as well as with cytochrome c- and caspase-3-dependent events. These events are sensitive to expression of constitutively active Akt. Mutation of Serine106 (Ser106), which is flanked by a putative Akt motif, hinders the association of the Bcl-XS protein with Akt, but promotes its association with VDAC. The dephosphorylation mimic, Bcl-XS(Ser106Ala), induces caspase-dependent PC12 and neuronal cell apoptosis. In contrast, Bcl-XS(Ser106Ala) induces a significant loss of VDAC expression, and cytochrome c- and caspase-independent toxicity in the non-neuronal HEK293A cells. We link haloperidol and Akt to Bcl-XS-sensitive toxicity via cell line-dependent mitochondrial events centering on VDAC. This clearly mitigates the chronic use of haloperidol in neuropsychiatric populations, but supports its use as a potential acute therapeutic in cancer, where apoptosis is desirable.
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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/Antipsychotic Agents,
http://linkedlifedata.com/resource/pubmed/chemical/Caspase 3,
http://linkedlifedata.com/resource/pubmed/chemical/Cytochromes c,
http://linkedlifedata.com/resource/pubmed/chemical/Haloperidol,
http://linkedlifedata.com/resource/pubmed/chemical/Proto-Oncogene Proteins c-akt,
http://linkedlifedata.com/resource/pubmed/chemical/Voltage-Dependent Anion Channels,
http://linkedlifedata.com/resource/pubmed/chemical/bcl-X Protein
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| pubmed:status |
MEDLINE
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| pubmed:month |
Jan
|
| pubmed:issn |
1873-3913
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| pubmed:author | |
| pubmed:issnType |
Electronic
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| pubmed:volume |
21
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| pubmed:owner |
NLM
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| pubmed:authorsComplete |
Y
|
| pubmed:pagination |
161-8
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| pubmed:dateRevised |
2009-11-19
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| pubmed:meshHeading |
pubmed-meshheading:18951975-Analysis of Variance,
pubmed-meshheading:18951975-Animals,
pubmed-meshheading:18951975-Antipsychotic Agents,
pubmed-meshheading:18951975-Apoptosis,
pubmed-meshheading:18951975-Caspase 3,
pubmed-meshheading:18951975-Cell Line,
pubmed-meshheading:18951975-Cytochromes c,
pubmed-meshheading:18951975-Haloperidol,
pubmed-meshheading:18951975-Humans,
pubmed-meshheading:18951975-Mitochondria,
pubmed-meshheading:18951975-Mutagenesis, Site-Directed,
pubmed-meshheading:18951975-PC12 Cells,
pubmed-meshheading:18951975-Phosphorylation,
pubmed-meshheading:18951975-Proto-Oncogene Proteins c-akt,
pubmed-meshheading:18951975-Rats,
pubmed-meshheading:18951975-Signal Transduction,
pubmed-meshheading:18951975-Voltage-Dependent Anion Channels,
pubmed-meshheading:18951975-bcl-X Protein
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| pubmed:year |
2009
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| pubmed:articleTitle |
Haloperidol disrupts Akt signalling to reveal a phosphorylation-dependent regulation of pro-apoptotic Bcl-XS function.
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| pubmed:affiliation |
Cell Signalling Laboratory, Neuropsychiatry Research Unit, University of Saskatchewan, Saskatoon (SK), Canada.
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| pubmed:publicationType |
Journal Article,
Research Support, Non-U.S. Gov't
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