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Article

Downregulation of thymidylate synthase with arsenic trioxide in lung adenocarcinoma

  • Authors:
    • Sze-Kwan Lam
    • Judith Choi-Wo Mak
    • Chun-Yan Zheng
    • Yuan-Yuan Li
    • Yok-Lam Kwong
    • James Chung-Man Ho
  • View Affiliations / Copyright

    Affiliations: Division of Respiratory Medicine, The University of Hong Kong, Queen Mary Hospital, Hong Kong SAR, P.R. China, Division of Haematology, Medical Oncology and Bone Marrow Transplantation, The University of Hong Kong, Queen Mary Hospital, Hong Kong SAR, P.R. China, Department of Medicine, The University of Hong Kong, Queen Mary Hospital, Pokfulam, Hong Kong SAR, P.R. China
  • Pages: 2093-2102
    |
    Published online on: April 2, 2014
       https://doi.org/10.3892/ijo.2014.2364
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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.
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Copy and paste a formatted citation
Spandidos Publications style
Lam S, Mak JC, Zheng C, Li Y, Kwong Y and Ho JC: Downregulation of thymidylate synthase with arsenic trioxide in lung adenocarcinoma. Int J Oncol 44: 2093-2102, 2014.
APA
Lam, S., Mak, J.C., Zheng, C., Li, Y., Kwong, Y., & Ho, J.C. (2014). Downregulation of thymidylate synthase with arsenic trioxide in lung adenocarcinoma. International Journal of Oncology, 44, 2093-2102. https://doi.org/10.3892/ijo.2014.2364
MLA
Lam, S., Mak, J. C., Zheng, C., Li, Y., Kwong, Y., Ho, J. C."Downregulation of thymidylate synthase with arsenic trioxide in lung adenocarcinoma". International Journal of Oncology 44.6 (2014): 2093-2102.
Chicago
Lam, S., Mak, J. C., Zheng, C., Li, Y., Kwong, Y., Ho, J. C."Downregulation of thymidylate synthase with arsenic trioxide in lung adenocarcinoma". International Journal of Oncology 44, no. 6 (2014): 2093-2102. https://doi.org/10.3892/ijo.2014.2364
Copy and paste a formatted citation
x
Spandidos Publications style
Lam S, Mak JC, Zheng C, Li Y, Kwong Y and Ho JC: Downregulation of thymidylate synthase with arsenic trioxide in lung adenocarcinoma. Int J Oncol 44: 2093-2102, 2014.
APA
Lam, S., Mak, J.C., Zheng, C., Li, Y., Kwong, Y., & Ho, J.C. (2014). Downregulation of thymidylate synthase with arsenic trioxide in lung adenocarcinoma. International Journal of Oncology, 44, 2093-2102. https://doi.org/10.3892/ijo.2014.2364
MLA
Lam, S., Mak, J. C., Zheng, C., Li, Y., Kwong, Y., Ho, J. C."Downregulation of thymidylate synthase with arsenic trioxide in lung adenocarcinoma". International Journal of Oncology 44.6 (2014): 2093-2102.
Chicago
Lam, S., Mak, J. C., Zheng, C., Li, Y., Kwong, Y., Ho, J. C."Downregulation of thymidylate synthase with arsenic trioxide in lung adenocarcinoma". International Journal of Oncology 44, no. 6 (2014): 2093-2102. https://doi.org/10.3892/ijo.2014.2364
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