The Ras Inhibitor S-trans,trans-Farnesylthiosalicylic Acid Chemosensitizes Human Tumor Cells Without Causing Resistance

Ras transformation requires Ras membrane anchorage, which is promoted by a farnesylcysteine carboxymethyl ester and by additional sequences specific to each Ras isoform. We showed previously that S -trans, trans -farnesylthiosalicylic acid (FTS) disrupts Ras membrane anchorage and that this disturba...

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Bibliographic Details
Published in:Clinical cancer research 2002-02, Vol.8 (2), p.555-565
Main Authors: Gana-Weisz, Mali, Halaschek-Wiener, Julius, Jansen, Burkhard, Elad, Galit, Haklai, Ronit, Kloog, Yoel
Format: Article
Language:English
Subjects:
Actins - metabolism
Animals
Antineoplastic agents
Antineoplastic Agents - pharmacology
Antineoplastic Combined Chemotherapy Protocols - pharmacology
Biological and medical sciences
Blotting, Western
Caveolin 1
Caveolins - biosynthesis
Chemotherapy
Deoxycytidine - analogs & derivatives
Deoxycytidine - pharmacology
Dose-Response Relationship, Drug
Down-Regulation
Doxorubicin - pharmacology
Drug Resistance, Neoplasm
Enzyme Inhibitors - pharmacology
Farnesol - analogs & derivatives
Farnesol - pharmacology
Humans
MAP Kinase Signaling System
Medical sciences
Mice
Mice, Nude
Mitogen-Activated Protein Kinases - biosynthesis
Phalloidine - pharmacology
Pharmacology. Drug treatments
ras Proteins - antagonists & inhibitors
Rats
Salicylates - pharmacology
Time Factors
Tumor Cells, Cultured
Up-Regulation
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Summary:Ras transformation requires Ras membrane anchorage, which is promoted by a farnesylcysteine carboxymethyl ester and by additional sequences specific to each Ras isoform. We showed previously that S -trans, trans -farnesylthiosalicylic acid (FTS) disrupts Ras membrane anchorage and that this disturbance contributes to inhibition of cell transformation and tumor growth. Most tumor cells develop resistance to anticancer agents. Here we examined whether tumor cells develop resistance to FTS and evaluated the therapeutic potential of FTS combined with cytotoxic drugs, because oncogenic Ras promotes antiapoptotic signals in tumors of epithelial origin. We showed that Panc-1 pancreatic cancer cells, SW480 colon cancer cells, and H- ras (EJ)-transformed Rat-1 fibroblasts exposed to FTS for prolonged periods (>6 months) do not escape FTS-induced growth inhibition and do not develop drug resistance. These cells continued to express reduced amounts of Ras, exhibit a reversed phenotype, and show an altered response to the cytotoxic drugs doxorubicin and gemcitabine. FTS-treated Panc-1 or SW480 cells acquired sensitivity to the cytotoxic drugs, whereas FTS-treated EJ cells lost sensitivity to doxorubicin, reflecting the opposite effects of oncogenic Ras on the survival of epithelial cells and fibroblasts. Treatment with FTS led to a marked increase in sensitivity to gemcitabine of the formerly resistant SW480 cells and a 100-fold increase in sensitivity to gemcitabine of Panc-1 cells. Such treatment in mice with preexisting Panc-1 tumors provided a synergistic effect of FTS and gemcitabine, leading to enhanced inhibition of tumor growth and a 65% increase in survival rate.
ISSN:1078-0432
1557-3265