Abstract
Recent strategies to sensitize radioresistant tumours are based on combining γ-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 γ-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 γ-ray therapy.
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Acknowledgements
This work was supported by the Institut National de la Santé et de la Recherche Médicale and by the French ETOILE project (Espace de Traitement Oncologique par les Ions Légers). We thank Colette Berthet and all the technicians from the Biochemical Laboratory of the Cardiovascular and Pneumological Hospital (Lyon, France) for ceramide and glutathione quantification, and also the technicians from the haematology laboratory (Lyon-Sud Hospital Center) for their help with flow cytometry. We are grateful to the personnel of the Radiotherapy Department (under Dr P. Romestaing) for allowing us access to the irradiators of the Lyon-Sud Hospital Center.
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Alphonse, G., Bionda, C., Aloy, MT. et al. Overcoming resistance to γ-rays in squamous carcinoma cells by poly-drug elevation of ceramide levels. Oncogene 23, 2703–2715 (2004). https://doi.org/10.1038/sj.onc.1207357
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DOI: https://doi.org/10.1038/sj.onc.1207357
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