Document Detail


Pharmacological inhibition of HSP90 and ras activity as a new strategy in the treatment of HNSCC.
MedLine Citation:
PMID:  22566192     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Advanced head and neck squamous cell cancer (HNSCC) is currently treated with taxane-based chemotherapy. We have previously shown that docetaxel (DTX) induces a ras-dependent survival signal that can be antagonized by farnesyl transferase inhibitors (FTI) such as tipifarnib (TIP). Here we show that the synergistic TIP/DTX combination determines synergistic apoptotic conditions but, at the same time, it modulates the expression of the components of the multichaperone complex that is, in turn, involved in the regulation of the stability of members of the ras-mediated pathway. Therefore, we have stably transfected HNSCC KB and Hep-2 cells with a plasmid encoding for HSP90. The expression of the protein was increased in both transfected cell lines but its activation status was increased in Hep-2 clones and decreased in KB clones. On the basis of these results, we have treated both parental and HSP90-transfected cells with a HSP90 inhibitor geldanamycin (GA). We have found that the antiproliferative activity of GA is dependent upon the activation status of HSP90 and that it is strongly synergistic when added in combination with TIP but not with DTX in cells overexpressing HSP90 and even more in cells with increased HSP90 activity. These data were paralleled by the decreased expression and activity of the components belonging to the ras→mediated signal transduction pathway. The present results suggest that multichaperone complex activation could be a resistance mechanism to the anti-proliferative and apoptotic effects induced by TIP and that the combination of FTIs such as TIP with GA could be a suitable therapeutic strategy in the treatment of HSP90-overexpressing HNSCC.
Authors:
Gabriella Misso; Gaia Giuberti; Angela Lombardi; Anna Grimaldi; Filippo Ricciardiello; Antonio Giordano; Pierosandro Tagliaferri; Alberto Abbruzzese; Michele Caraglia
Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Journal of cellular physiology     Volume:  228     ISSN:  1097-4652     ISO Abbreviation:  J. Cell. Physiol.     Publication Date:  2013 Jan 
Date Detail:
Created Date:  2012-10-08     Completed Date:  2012-12-31     Revised Date:  2013-05-28    
Medline Journal Info:
Nlm Unique ID:  0050222     Medline TA:  J Cell Physiol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  130-41     Citation Subset:  IM    
Copyright Information:
Copyright © 2012 Wiley Periodicals, Inc.
Affiliation:
Department of Biochemistry and Biophysics, Second University of Naples, Via Costantinopoli, Naples, Italy.
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MeSH Terms
Descriptor/Qualifier:
Antineoplastic Agents / pharmacology*,  therapeutic use
Apoptosis / drug effects
Benzoquinones / pharmacology,  therapeutic use
Carcinoma, Squamous Cell / drug therapy*,  metabolism
Cell Line, Tumor
Cell Survival / drug effects
Drug Synergism
Gene Expression Regulation, Neoplastic / drug effects
HSP90 Heat-Shock Proteins / antagonists & inhibitors*,  genetics,  metabolism
Head and Neck Neoplasms / drug therapy*,  metabolism
Humans
Lactams, Macrocyclic / pharmacology,  therapeutic use
Quinolones / pharmacology,  therapeutic use
Signal Transduction / drug effects
Taxoids / pharmacology,  therapeutic use
ras Proteins / antagonists & inhibitors*,  genetics,  metabolism
Chemical
Reg. No./Substance:
0/Antineoplastic Agents; 0/Benzoquinones; 0/HSP90 Heat-Shock Proteins; 0/Lactams, Macrocyclic; 0/Quinolones; 0/Taxoids; 15H5577CQD/docetaxel; 192185-72-1/tipifarnib; EC 3.6.5.2/ras Proteins; Z3K3VJ16KU/geldanamycin

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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