Document Detail


Blockade of the Ras pathway by manumycin, a farnesyltransferase inhibitor, overcomes the resistance of myeloma plasma cells to Fas-induced apoptosis.
MedLine Citation:
PMID:  15750764     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Ras activation (by point mutation or binding of IL-6) is frequently observed in multiple myeloma (MM). As farnesylation of Ras protein by farnesyltransferase is a critical step for Ras functional activity, farnesyltransferase inhibitors (FTI) have emerged as potential anti-cancer agents. Manumycin, a natural FTI, prevents proliferation and induces apoptosis of myeloma cells refractory to Fasand drug-induced cell death. Fas pathway analysis showed that Fas-resistant apoptosis of Fas-positive myeloma cells parallels FLIP (FLICE/caspase-8-inhibitory protein) expression. Treatment of fresh purified myeloma cells, myeloma cell clone-2 and U266 cell line with manumycin induced down-regulation of FLIP expression with concomitant expression of Apo 2.7 antigen, the marker of early apoptosis. Down-regulation of FLIP mRNA levels in drug-treated cells was associated to suppression of the transcription factor NF-kappaB that plays a central role in chemoresistance, survival and proliferation of myeloma cells. Further analysis showed that manumycin-induced apoptosis involved caspases activation and was prevented by the addition of caspases specific inhibitors. Finally, pretreatment of Fas-resistant/FLIP-positive cells with manumycin sensitised them to Fas-triggered apoptosis. Overall results indicate that manumycin-induced apoptosis involves Fas pathway. FTIs may thus be proposed as a promising class of anti-cancer agents which can boost the cytotoxic effect of conventional drugs by overcoming NF-kappaB activation and Fas-resistant apoptosis.
Authors:
M A Frassanito; L Mastromauro; A Cusmai; F Dammacco
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Clinical and experimental medicine     Volume:  4     ISSN:  1591-9528     ISO Abbreviation:  Clin. Exp. Med.     Publication Date:  2005 Mar 
Date Detail:
Created Date:  2005-03-07     Completed Date:  2009-10-27     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  100973405     Medline TA:  Clin Exp Med     Country:  Italy    
Other Details:
Languages:  eng     Pagination:  174-82     Citation Subset:  IM    
Affiliation:
Department of Internal Medicine and Oncology (DIMO), University of Bari Medical School, Piazza G. Cesare 11, I-70124 Bari, Italy.
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MeSH Terms
Descriptor/Qualifier:
Apoptosis / drug effects*
Enzyme Inhibitors / pharmacology*
Fas Ligand Protein / drug effects*
Gene Expression Regulation, Neoplastic
Genes, ras / drug effects*
Humans
Multiple Myeloma / drug therapy
Plasma Cells
Polyenes / pharmacology*
Polyunsaturated Alkamides / pharmacology*
Signal Transduction
Chemical
Reg. No./Substance:
0/Enzyme Inhibitors; 0/Fas Ligand Protein; 0/Polyenes; 0/Polyunsaturated Alkamides; 52665-74-4/manumycin

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