title: Downregulation of thymidylate synthase with arsenic trioxide in lung adenocarcinoma.
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.
authors.affiliation: Division of Respiratory Medicine, The University of Hong Kong, Queen Mary Hospital, Hong Kong SAR, P.R. China.
authors.forename: Sze-Kwan
authors.initials: SK
authors.lastname: Lam
authors.affiliation: Division of Respiratory Medicine, The University of Hong Kong, Queen Mary Hospital, Hong Kong SAR, P.R. China.
authors.forename: Judith Choi-Wo
authors.initials: JC
authors.lastname: Mak
authors.affiliation: Division of Respiratory Medicine, The University of Hong Kong, Queen Mary Hospital, Hong Kong SAR, P.R. China.
authors.forename: Chun-Yan
authors.initials: CY
authors.lastname: Zheng
authors.affiliation: Division of Respiratory Medicine, The University of Hong Kong, Queen Mary Hospital, Hong Kong SAR, P.R. China.
authors.forename: Yuan-Yuan
authors.initials: YY
authors.lastname: Li
authors.affiliation: Division of Haematology, Medical Oncology and Bone Marrow Transplantation, The University of Hong Kong, Queen Mary Hospital, Hong Kong SAR, P.R. China.
authors.forename: Yok-Lam
authors.initials: YL
authors.lastname: Kwong
authors.affiliation: Department of Medicine, The University of Hong Kong, Queen Mary Hospital, Pokfulam, Hong Kong SAR, P.R. China.
authors.forename: James Chung-Man
authors.initials: JC
authors.lastname: Ho
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy* / Q000473:pathology; D000077192:Adenocarcinoma of Lung; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D000077237:Arsenic Trioxide; D001152:Arsenicals / Q000494:pharmacology* / Q000627:therapeutic use; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D055785:Gene Knockdown Techniques; D006801:Humans; D008114:Liver Neoplasms, Experimental; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000473:pathology; D051379:Mice; D008819:Mice, Nude; D010087:Oxides / Q000494:pharmacology* / Q000627:therapeutic use; D013940:Thymidylate Synthase / Q000235:genetics* / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D001152:Arsenicals; D010087:Oxides; D013940:Thymidylate Synthase; D000077237:Arsenic Trioxide