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The novel thymidylate synthase inhibitor trifluorothymidine (TFT) and TRAIL synergistically eradicate non-small cell lung cancer cells.
- Source :
-
Cancer chemotherapy and pharmacology [Cancer Chemother Pharmacol] 2014 Jun; Vol. 73 (6), pp. 1273-83. Date of Electronic Publication: 2014 Apr 18. - Publication Year :
- 2014
-
Abstract
- Purpose: TRAIL, a tumor selective anticancer agent, may be used for the treatment of non-small cell lung cancer (NSCLC). However, TRAIL resistance is frequently encountered. Here, the combined use of TRAIL with trifluorothymidine (TFT), a thymidylate synthase inhibitor, was examined for sensitizing NSCLC cells to TRAIL.<br />Methods: Interactions between TRAIL and TFT were studied in NSCLC cells using growth inhibition and apoptosis assays. Western blotting and flow cytometry were used to investigate underlying mechanisms.<br />Results: The combined treatment of TFT and TRAIL showed synergistic cytotoxicity in A549, H292, H322 and H460 cells. For synergistic activity, the sequence of administration was important; TFT treatment followed by TRAIL exposure did not show sensitization. Combined TFT and TRAIL treatment for 24 h followed by 48 h of TFT alone was synergistic in all cell lines, with combination index values below 0.9. The treatments affected cell cycle progression, with TRAIL inducing a G1 arrest and TFT, a G2/M arrest. TFT activated Chk2 and reduced Cdc25c levels known to cause G2/M arrest. TRAIL-induced caspase-dependent apoptosis was enhanced by TFT, whereas TFT alone mainly induced caspase-independent death. TFT increased the expression of p53 and p21/WAF1, and p53 was involved in the increase of TRAIL-R2 surface expression. TFT also caused downregulation of cFLIP and XIAP and increased Bax expression.<br />Conclusions: TFT enhances TRAIL-induced apoptosis in NSCLC cells by sensitizing the apoptotic machinery at different levels in the TRAIL pathway. Our findings suggest a possible therapeutic benefit of the combined use of TFT and TRAIL in NSCLC.
- Subjects :
- Antimetabolites administration & dosage
Antimetabolites pharmacology
Apoptosis drug effects
Carcinoma, Non-Small-Cell Lung metabolism
Carcinoma, Non-Small-Cell Lung pathology
Caspases metabolism
Cathepsin B metabolism
Cell Cycle drug effects
Cell Death drug effects
Cell Line, Tumor
Drug Synergism
Humans
Lung Neoplasms metabolism
Lung Neoplasms pathology
RNA Interference
RNA, Small Interfering metabolism
TNF-Related Apoptosis-Inducing Ligand administration & dosage
Thymidylate Synthase antagonists & inhibitors
Trifluridine administration & dosage
Antineoplastic Combined Chemotherapy Protocols pharmacology
Carcinoma, Non-Small-Cell Lung drug therapy
Lung Neoplasms drug therapy
TNF-Related Apoptosis-Inducing Ligand pharmacology
Trifluridine pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 1432-0843
- Volume :
- 73
- Issue :
- 6
- Database :
- MEDLINE
- Journal :
- Cancer chemotherapy and pharmacology
- Publication Type :
- Academic Journal
- Accession number :
- 24744163
- Full Text :
- https://doi.org/10.1007/s00280-014-2465-1