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Downregulation of thymidylate synthase with arsenic trioxide in lung adenocarcinoma.
- Source :
-
International journal of oncology [Int J Oncol] 2014 Jun; Vol. 44 (6), pp. 2093-102. Date of Electronic Publication: 2014 Apr 02. - Publication Year :
- 2014
-
Abstract
- Thymidylate synthase (TYMS) is an important chemotherapeutic target in non-small cell lung cancer (NSCLC). Arsenic trioxide (ATO) has been shown to suppress TYMS in a colonic cancer model. We examined the effects of TYMS suppression by ATO in lung adenocarcinoma. A panel of 4 lung adenocarcinoma cell lines was used to determine the effects of ATO treatment on cell viability, TYMS expression (protein and mRNA), E2F1 protein expression and TYMS activity. TYMS knockdown and overexpression were performed. Tumor growth inhibition in vivo was studied using a nude mouse xenograft model. ATO showed antiproliferative effects with clinically achievable concentrations (around 1.1-6.9 µM) in 4 lung adenocarcinoma cell lines. Downregulation of TYMS protein and mRNA expression, reduced TYMS activity, and suppressed E2F1 expression were demonstrated in lung adenocarcinoma with ATO. Cell viability was reduced by 15-50% with TYMS knockdown. Overexpression of TYMS led to a 2.7-fold increase in IC50 value with ATO treatment in H358 cells, but not in H23 cells. Using a xenograft model with H358 cell line, relative tumor volume was reduced to 44% that of the control following 8 days of treatment with 7.5 mg/kg ATO, and associated with significant downregulation of TYMS protein expression. In conclusion, ATO has potent in vitro and in vivo activity in lung adenocarcinoma, and is partially mediated by transcriptional downregulation of TYMS.
- Subjects :
- Adenocarcinoma pathology
Adenocarcinoma of Lung
Animals
Antineoplastic Agents therapeutic use
Apoptosis drug effects
Arsenic Trioxide
Arsenicals therapeutic use
Cell Survival drug effects
Dose-Response Relationship, Drug
Female
Gene Expression Regulation, Neoplastic drug effects
Gene Knockdown Techniques
Humans
Liver Neoplasms, Experimental
Lung Neoplasms pathology
Mice
Mice, Nude
Oxides therapeutic use
Xenograft Model Antitumor Assays
Adenocarcinoma drug therapy
Antineoplastic Agents pharmacology
Arsenicals pharmacology
Lung Neoplasms drug therapy
Oxides pharmacology
Thymidylate Synthase genetics
Thymidylate Synthase metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1791-2423
- Volume :
- 44
- Issue :
- 6
- Database :
- MEDLINE
- Journal :
- International journal of oncology
- Publication Type :
- Academic Journal
- Accession number :
- 24691991
- Full Text :
- https://doi.org/10.3892/ijo.2014.2364