title: The Ras inhibitor S-trans,trans-farnesylthiosalicylic acid chemosensitizes human tumor cells without causing resistance.
abstract: 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.
authors.affiliation: Department of Neurobiochemistry, The George S. Wise Faculty of Life Sciences, Tel-Aviv University, 69978 Tel Aviv, Israel.
authors.forename: Mali
authors.initials: M
authors.lastname: Gana-Weisz
authors.forename: Julius
authors.initials: J
authors.lastname: Halaschek-Wiener
authors.forename: Burkhard
authors.initials: B
authors.lastname: Jansen
authors.forename: Galit
authors.initials: G
authors.lastname: Elad
authors.forename: Ronit
authors.initials: R
authors.lastname: Haklai
authors.forename: Yoel
authors.initials: Y
authors.lastname: Kloog
mesh_terms: D000199:Actins / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology; D015153:Blotting, Western; D051242:Caveolin 1; D022461:Caveolins / Q000096:biosynthesis; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D004317:Doxorubicin / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005204:Farnesol / Q000031:analogs & derivatives* / Q000494:pharmacology*; D006801:Humans; D020935:MAP Kinase Signaling System; D051379:Mice; D008819:Mice, Nude; D020928:Mitogen-Activated Protein Kinases / Q000096:biosynthesis; D010590:Phalloidine / Q000494:pharmacology; D051381:Rats; D012459:Salicylates / Q000494:pharmacology*; D013997:Time Factors; D014407:Tumor Cells, Cultured; D015854:Up-Regulation; D018631:ras Proteins / Q000037:antagonists & inhibitors*; D000093542:Gemcitabine
chemical_list: D000199:Actins; D000970:Antineoplastic Agents; D051242:Caveolin 1; D022461:Caveolins; D004791:Enzyme Inhibitors; D012459:Salicylates; C093323:farnesylthiosalicylic acid; D003841:Deoxycytidine; D010590:Phalloidine; D005204:Farnesol; D004317:Doxorubicin; D020928:Mitogen-Activated Protein Kinases; D018631:ras Proteins; D000093542:Gemcitabine