Overcoming resistance to γ-rays in squamous carcinoma cells by poly-drug elevation of ceramide levels
| Autor: | Robert Rousson, Gersende Alphonse, Dominique Ardail, Claire Rodriguez-Lafrasse, M.-T. Aloy, Clara Bionda |
|---|---|
| Rok vydání: | 2004 |
| Předmět: |
Cancer Research
Ceramide Time Factors Blotting Western Mitosis Apoptosis Biology Ceramides medicine.disease_cause Propanolamines chemistry.chemical_compound Cell Line Tumor Genetics medicine Humans Molecular Biology Chromatography High Pressure Liquid Caspase 8 Sphingolipids Myristates Caspase 3 Dose-Response Relationship Radiation Lipid signaling Cell cycle Flow Cytometry Caspase Inhibitors Glutathione Sphingolipid N-Acetylneuraminic Acid Mitochondria Squamous carcinoma Cell biology Enzyme Activation Kinetics stomatognathic diseases Epidermoid carcinoma chemistry Gamma Rays Glucosyltransferases Head and Neck Neoplasms Caspases Carcinoma Squamous Cell Cancer research Reactive Oxygen Species Carcinogenesis Oxidation-Reduction |
| Zdroj: | Oncogene. 23:2703-2715 |
| ISSN: | 1476-5594 0950-9232 |
| DOI: | 10.1038/sj.onc.1207357 |
| Popis: | Recent strategies to sensitize radioresistant tumours are based on combining gamma-irradiation with inducers of apoptosis. We report that the combination of three inhibitors of sphingolipid metabolism, DL-threo-1-phenyl-2-decanoylamino-3-morpholino-1-propanol.HCl(DL-PDMP)+imipramine +/- D-erythro-2-(N-myristoylamino)-1-phenyl-1-propanol (D-MAPP), with 10-Gy irradiation triggers both mitotic and apoptotic killing in radioresistant SQ20B squamous carcinoma cells. In these cells, apoptosis is defective due to a lack of ceramide generation upstream, which cannot be explained by sphingomyelinase (neutral and acidic) deficiency or rapid derivation to the sphingolipid pathway. We present evidence of a functional transduction death pathway when ceramide generation is restored, which involves the mitochondrial-mediated pathway coupled to alterations in redox status and to executive caspases activation. The poly-drug treatment restored apoptosis to levels similar to those observed in radiosensitive SCC61 squamous carcinoma cells. Simultaneous exposure to gamma-irradiation and poly-drug treatment acted synergistically in SQ20B cells to produce a marked increase in both mitochondrial dysfunction and caspase cleavage, which led to a 7.8-fold increase in apoptosis within 48 h, relative to irradiated cells. Moreover, the results suggest that the ceramide released by irradiation or poly-drug treatment converges upon common cellular targets. Modulation of endogenous ceramide levels by inhibitors of sphingolipid metabolism may represent a new cellular target for the sensitization of radioresistant tumours to gamma-ray therapy. |
| Databáze: | OpenAIRE |
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