Clonal variability of radiation-induced cisplatin resistant HeLa cells.
Low-dose fractionated gamma-irradiation (3 cycles of 5x2 Gy) induces moderate cisplatin resistance in HeLa cells which is associated with alterations of the caspase-dependent apoptotic pathway (2). There is a considerable heterogeneity in cell survival among isolated resistant clones (Rf values between 1.4 to 2.4) and in the propensity of the cells to enter apoptosis. These variations are associated with altered activation of the apoptotic pathway by members of the TNF family. The membrane receptor CD95 (Apo-1/Fas), which is upregulated immediately after cisplatin exposure in parental HeLa cells, is expressed at various levels in the resistant clones. There are also changes in the formation of the inhibitor protein I kappa B, which regulates the antiapoptotic transcription factor NF kappa B. Since the response to radiation is unchanged, the results collectively suggest that changes in the activation of the caspase-dependent signalling cascade are involved in the death pathway initiated by cisplatin but not by radiation damage.
Eichholtz-Wirth
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H
GSF-National Research Center for Environment and Health, Institute of Radiology, Neuherberg, Germany.
Marx
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K
D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology / Q000528:radiation effects; D002470:Cell Survival / Q000187:drug effects / Q000528:radiation effects; D002945:Cisplatin / Q000494:pharmacology*; D002999:Clone Cells; D019008:Drug Resistance, Neoplasm / Q000528:radiation effects*; D005720:Gamma Rays; D014644:Genetic Variation; D006367:HeLa Cells / Q000187:drug effects / Q000528:radiation effects; D006801:Humans; D016328:NF-kappa B / Q000096:biosynthesis; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology*; D051841:Transcription Factor RelB; D014157:Transcription Factors; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D019014:fas Receptor / Q000378:metabolism
D000970:Antineoplastic Agents; D016328:NF-kappa B; D011518:Proto-Oncogene Proteins; C497593:RELB protein, human; D011838:Radiation-Sensitizing Agents; D014157:Transcription Factors; D014409:Tumor Necrosis Factor-alpha; D019014:fas Receptor; D051841:Transcription Factor RelB; D002945:Cisplatin