| Anti-apoptotic effect of HIV protease inhibitors via direct inhibition of calpain. | |
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MedLine Citation:
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PMID: 14555228 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Treatment with drugs designed to inhibit the HIV protease ameliorates immune functions in AIDS patients, reducing cell deletion by apoptosis even in the absence of inhibition of viral spread. This suggests that they interact with the intrinsic apoptotic signaling. We found that caspases, the main executioner of the apoptotic process, are not directly inhibited. In search for the mechanism responsible for their anti-apoptotic effect, we have found that indinavir and ritonavir are able to inhibit apoptosis only in those cell systems where apoptosis involves the activation of calpains. They directly inhibit a calpain-like activity expressed in lysates from apoptotic cells, to the same extent as commercially available calpain inhibitor 1. In in vitro assays with purified calpains, indinavir and ritonavir strongly inhibit m-calpain, and moderately mu-calpain. These results have great therapeutic implications, going beyond AIDS treatment, since many degenerative disorders involve abnormal calpain activation, indicating calpain as an ideal pharmacological target. Indinavir and ritonavir, potent m-calpain inhibitors, largely used since several years on humans without important negative side effects, may become powerful tools against those pathologies. |
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Authors:
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Lina Ghibelli; Fabio Mengoni; Miriam Lichtner; Simona Coppola; Milena De Nicola; Antonio Bergamaschi; Claudio Mastroianni; Vincenzo Vullo |
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Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't |
Journal Detail:
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Title: Biochemical pharmacology Volume: 66 ISSN: 0006-2952 ISO Abbreviation: Biochem. Pharmacol. Publication Date: 2003 Oct |
Date Detail:
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Created Date: 2003-10-13 Completed Date: 2003-11-20 Revised Date: 2006-11-15 |
Medline Journal Info:
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Nlm Unique ID: 0101032 Medline TA: Biochem Pharmacol Country: England |
Other Details:
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Languages: eng Pagination: 1505-12 Citation Subset: IM |
Affiliation:
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Dipartimento di Biologia, Universita' di Roma Tor Vergata, via Ricerca Scientifica, 00133 Rome, Italy. ghibelli@uniroma2.it |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Apoptosis* Calpain / antagonists & inhibitors* Caspases / antagonists & inhibitors, metabolism HIV Protease Inhibitors / pharmacology* Humans Indinavir / pharmacology* Ritonavir / pharmacology |
| Chemical | |
Reg. No./Substance:
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0/HIV Protease Inhibitors; 0/Ritonavir; 150378-17-9/Indinavir; EC 3.4.22.-/Calpain; EC 3.4.22.-/Caspases |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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