1. Fumonisin B1 Inhibits Endoplasmic Reticulum Stress Associated-apoptosis After FoscanPDT Combined with C6-Pyridinium Ceramide or Fenretinide.
- Author
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Boppana NB, Kraveka JM, Rahmaniyan M, Li LI, Bielawska A, Bielawski J, Pierce JS, Delor JS, Zhang K, Korbelik M, and Separovic D
- Subjects
- Apoptosis drug effects, Carcinoma, Squamous Cell metabolism, Carcinoma, Squamous Cell pathology, Caspase 3 metabolism, Caspase Inhibitors pharmacology, Cell Line, Tumor, Combined Modality Therapy, Head and Neck Neoplasms metabolism, Head and Neck Neoplasms pathology, Humans, Radiation-Sensitizing Agents pharmacology, Squamous Cell Carcinoma of Head and Neck, Carcinoma, Squamous Cell drug therapy, Ceramides pharmacology, Endoplasmic Reticulum Stress drug effects, Fenretinide pharmacology, Fumonisins pharmacology, Head and Neck Neoplasms drug therapy, Mesoporphyrins pharmacology, Photochemotherapy methods, Pyridinium Compounds pharmacology
- Abstract
Background/aim: Combining an anticancer agent fenretinide (HPR) or C6-pyridinium ceramide (LCL29) with Foscan-mediated photodynamic therapy (FoscanPDT) is expected to augment anticancer benefits of each substance. We showed that treatment with FoscanPDT+HPR enhanced accumulation of C16-dihydroceramide, and that fumonisin B1 (FB), an inhibitor of ceramide synthase, counteracted caspase-3 activation and colony-forming ability of head and neck squamous cell carcinoma (HNSCC) cells. Because cancer cells appear to be more susceptible to increased levels of the endoplasmic reticulum (ER) stress than normal cells, herein we tested the hypothesis that FoscanPDT combined with HPR or LCL29 induces FB-sensitive ER stress-associated apoptosis that affects cell survival., Materials and Methods: Using an HNSCC cell line, we determined: cell survival by clonogenic assay, caspase-3 activity by spectrofluorometry, the expression of the ER markers BiP and CHOP by quantitative real-time polymerase chain reaction and western immunoblotting, and sphingolipid levels by mass spectrometry., Results: Similar to HPR+FoscanPDT, LCL29+FoscanPDT induced enhanced loss of clonogenicity and caspase-3 activation, that were both inhibited by FB. Our additional pharmacological evidence showed that the enhanced loss of clonogenicity after the combined treatments was singlet oxygen-, ER stress- and apoptosis-dependent. The combined treatments induced enhanced, FB-sensitive, up-regulation of BiP and CHOP, as well as enhanced accumulation of sphingolipids., Conclusion: Our data suggest that enhanced clonogenic cell killing after the combined treatments is dependent on oxidative- and ER-stress, apoptosis, and FB-sensitive sphingolipid production, and should help develop more effective mechanism-based therapeutic strategies., (Copyright© 2017, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)
- Published
- 2017
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