title: Combining an FPTase inhibitor with cisplatin facilitates induction of apoptosis in human A549 lung cancer cells.
abstract: Despite great efforts to develop efficacious curative treatments, the prognosis for lung cancer patients is poor. In the present study we compared the effects of cisplatin (CP), a strong DNA damaging compound, with those of roscovitine (ROSC), a selective inhibitor of cyclin-dependent kinases (CDKs), on wt p53-positive human A549 lung adenocarcinoma cells harboring a mutated K-RAS gene. Asynchronously growing A549 cells were relatively resistant to CP treatment for 24 h, but after exposure to CP at sufficiently high doses (> or = 20 microM) an accumulation of S-arrested cells was observed. However, after post-incubation of CP-treated cells in a drug-free medium for a further 48 h the number of living cells was markedly reduced. Combining CP with L-744,832, a small molecule FPTase inhibitor (FTI), slightly enhanced its anti-proliferative effect. Interestingly, FTI sensitized A549 cells to CP-induced apoptosis. ROSC inhibited A549 cells at the G/M transition, resulting in a marked decrease in the number of viable cells within 24 h, and prolonged treatment with ROSC for 48 h reduced the frequency of living cells by inducing apoptosis. The effects of ROSC (unlike those of CP) were more strongly enhanced by inhibition of the Ras protein processing pathway. Our preliminary results indicate that functional p53 contributes to the outcome of the therapy in human A549 cells by certain anti-cancer drugs.
authors.affiliation: Cell Cycle Regulation Group, Div.: Institute of Cancer Research, Dept. of Medicine I, Medical University of Vienna, Borschkegasse 8a, 1090 Vienna, Austria.
authors.forename: Franziska
authors.initials: F
authors.lastname: Weber
authors.forename: Peter
authors.initials: P
authors.lastname: Siska
authors.forename: Matthias
authors.initials: M
authors.lastname: Kramer
authors.forename: Nora
authors.initials: N
authors.lastname: Zulehner
authors.forename: Stefan
authors.initials: S
authors.lastname: Hackl
authors.forename: Józefa
authors.initials: J
authors.lastname: Wesierska-Gádek
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D000077192:Adenocarcinoma of Lung; D019883:Alkyl and Aryl Transferases / Q000037:antagonists & inhibitors*; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects*; D020169:Caspases / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002945:Cisplatin / Q000627:therapeutic use*; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D005434:Flow Cytometry; D006801:Humans; D015151:Immunoblotting; D008175:Lung Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D008715:Methionine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors; D016283:Proto-Oncogene Proteins p21(ras); D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D018631:ras Proteins / Q000037:antagonists & inhibitors
chemical_list: D000970:Antineoplastic Agents; C117307:KRAS protein, human; C096898:L 744832; D011518:Proto-Oncogene Proteins; D016159:Tumor Suppressor Protein p53; D008715:Methionine; D019883:Alkyl and Aryl Transferases; C064911:p21(ras) farnesyl-protein transferase; D020169:Caspases; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins; D002945:Cisplatin