Document Detail


A combined treatment of HeLa cells with the farnesyl protein transferase inhibitor L-744,832 and cisplatin significantly increases the therapeutic effect as compared to cisplatin monotherapy.
MedLine Citation:
PMID:  18022825     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Activating mutations of Ras that frequently occur during malignant transformation, enhance growth-promoting signal transduction, allowing cells to bypass stringent control of cell cycle progression, thereby rendering them highly proliferative. Abundantly expressed c-Ha-ras protein in human cervical HeLa cells is farnesylated and attached to the plasma membrane, inducing enhanced signal transduction. Exposure of HeLa cells to cisplatin very efficiently inhibits cell proliferation and induces apoptosis. Unfortunately, high doses of cisplatin are strongly cytotoxic, therefore, an alternative therapeutic strategy allowing dose reduction of cisplatin by inhibition of farnesylation could increase the curative effects of cisplatin, thereby benefiting cancer patients. We used two inhibitors of farnesyl protein transferase (FPTase), FTI, and L-744,832, to sensitize HeLa cells to the action of cisplatin. The combined administration of cisplatin and inhibitors of FPTase increased the cytostatic potency of cisplatin. L-744,832 exhibited a stronger synergistic effect in combination with cisplatin than FTI. Moreover, the efficiency of the combined therapy strongly depended on the treatment regimen: The highest efficiency was achieved after combined treatment for 24 h and post-incubation with an inhibitor of FPTase for 48 h. Following this optimized treatment, apoptosis was induced in approximately 50% of HeLa cells treated with 1 microM cisplatin, representing approximately a threefold increase as compared to cisplatin monotherapy. Combined treatment of HeLa cells with cisplatin and inhibitors of FPTase significantly increases the efficacy of the therapy and allows to reduce the dose of cisplatin. Importantly, best therapeutic effects can be achieved by post-treatment with inhibitors of FPTase.
Authors:
Józefa Wesierska-Gadek; Matthias P Kramer; Gerald Schmid
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Publication Detail:
Type:  Journal Article    
Journal Detail:
Title:  Journal of cellular biochemistry     Volume:  104     ISSN:  1097-4644     ISO Abbreviation:  J. Cell. Biochem.     Publication Date:  2008 May 
Date Detail:
Created Date:  2008-04-24     Completed Date:  2008-07-08     Revised Date:  2009-02-23    
Medline Journal Info:
Nlm Unique ID:  8205768     Medline TA:  J Cell Biochem     Country:  United States    
Other Details:
Languages:  eng     Pagination:  189-201     Citation Subset:  IM    
Affiliation:
Cell Cycle Regulation Group, Department of Medicine I, Institute of Cancer Research, Medical University of Vienna, Vienna, Austria. jozefa.gadek-wesierski@meduniwien.ac.at
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MeSH Terms
Descriptor/Qualifier:
Alkyl and Aryl Transferases / antagonists & inhibitors*
Antineoplastic Combined Chemotherapy Protocols / pharmacology*
Apoptosis / drug effects
Cisplatin / pharmacology*
Drug Synergism
Drug Therapy, Combination
Female
Hela Cells
Humans
Methionine / analogs & derivatives*,  pharmacology
Proto-Oncogene Proteins p21(ras)
Uterine Cervical Neoplasms / drug therapy,  pathology
Chemical
Reg. No./Substance:
0/L 744832; 15663-27-1/Cisplatin; 63-68-3/Methionine; EC 2.5.-/Alkyl and Aryl Transferases; EC 2.5.1.-/p21(ras) farnesyl-protein transferase; EC 3.6.5.2/Proto-Oncogene Proteins p21(ras)

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