Project title
鹽黴素與硝化甘油導致胸腺嘧啶合成酶及乙醛去氫酶1A1表現下降在增加人類非小細胞肺癌細胞對於化療藥物順鉑敏感性之角色
Internal ID
107-2314-B-002-236
Principal Investigator
Start Date
August 1, 2018
End Date
July 31, 2019
Investigators
林芸薇
Organizations
Partner Organizations
Role of Down-Regulation of Thymidylate Synthase (Ts) and Aldehyde Dehydrogenase 1a1 (Aldh1a1) Expression in Salinomycin and Nitroglycerin to Enhance the Drug Sensitivity of Cisplatin in Human Non-Small Cell Lung Cancer Cells = 鹽黴素與硝化甘油導致胸腺嘧啶合成酶及乙醛去氫酶1A1表現下降在增加人類非小細胞肺癌細胞對於化療藥物順鉑敏感性之角色
Description
Lung cancer remains a high-incidence, high-mortality malignancy, and approximately 85% lung cancer patients are non-small-cell lung cancer (NSCLC). The use of cytotoxic chemotherapies has resulted in improvements in both median overall survival and one-year survival rates compared with best supportive care. Cisplatin is typically used as first or second line regimen to treat NSCLC. Thymidylate synthase (TS) is an essential enzyme for the de novo synthesis of dTMP; we found that knocking down the expression of TS can sensitize lung cancer cells to cisplatin-induced cytotoxicity. Salinomycin was originally used to eliminate fungi, bacteria, and parasites. Salinomycin acts in different cellular membranes, including cytoplasmic and mitochondrial membranes, as an ionophore with a strict selectivity for monovalent cations and an extensive preference for potassium ions. Recent research has shown that salinomycin synergistically increases stem cell death of head and neck squamous cell carcinoma (HNSCC) in combination with cisplatin and paclitaxel. Our study found that salinomycin decreased TS expression in NSCLC cells, and enhanced the cisplatin-induced cytotoxicity and mutagenesis. However, the detail mechanism of salinomycin combined with cisplatin to enhance drugs sensitivity and toxicity in NSCLC cells is unclear. Aldehyde dehydrogenase 1A1 (ALDH1A1), which is a detoxifying enzyme that oxidizes intracellular aldehydes, and thereby confers resistance to alkylating agents, it also is one of the classic NSCLC stem cell markers. Previous report had shown that the antianginal drug nitroglycerin can inhibit ALDH1A1 expression. Therefore, we will determine how salinomycin and cisplatin combination in regulating TS expression in NSCLC cells. The physiological effect of salinomycin-mediated TS down-regulation to enhance drugs sensitivity of chemotherapeutic agents will be investigated. We will determine whether salinomycin combined with nitroglycerin can enhance the drug sensitivity to cisplatin through increasing apoptosis, and through suppression of the TS and ALDH1A1expression. In addition, we want to know whether salinomycin combined with nitroglycerin can increase cisplatin accumulation in cytoplasm of lung cancer cells, and increase of platinum-induced DNA adducts formation to enhance cisplatin-induced mutagenicity.The final goal of this project is to understand how salinomycin and cisplatin to modulate TS and ALDH1A1 expression, and its role in regulating synergistic cytotoxic and mutagenesis effects in NSCLC cell lines, and the role of nitroglycerin in suppression of TS and ALDH1A1expression to enhance the cytotoxicity of cisplatin and salinimycin in NSCLC cells. We hope that these results can provide further evidence for an experimental rationale to use salinomycin and nitroglycerin as a regimen in combinatorial therapy in a variety of NSCLC, to enhance the therapeutic response and to reduce the chemotherapy drugs dosage and side effects in NSCLC patients.