Project title
滅糖敏向下調控核酸代謝酵素Thymidine Phosphorylase 表現在增加肺癌細胞對化療藥物順鉑與標靶藥物艾瑞莎敏感性的分子機轉
Internal ID
NSC 102-2314-B-002 -095
Principal Investigator
Start Date
August 1, 2013
End Date
July 31, 2014
Investigators
林芸薇
Organizations
Partner Organizations
Molecular Mechanism of Metformin Mediated Down-Regulation of Thymidine Phosphorylase Expression in Enhancing Sensitivity of Cisplatin and Gefitinib to Human Lung Cancer Cells = 滅糖敏向下調控核酸代謝酵素Thymidine Phosphorylase 表現在增加肺癌細胞對化療藥物順鉑與標靶藥物艾瑞莎敏感性的分子機轉
Description
Metformin, a widely used and well tolerated antidiabetic agent, exerts remarkable antitumoral effects on cancer cells and mouse models. Currently, a number of clinical trials examining the use of metformin as a cancer therapy are underway including studies in breast, prostate, colon, and pancreatic cancer patients. Metformin is able to reduce overall tumor burden in a tobacco carcinogen-induced model of lung cancer. However, its effect on lung cancer, particularly on non-small cell lung cancer (NSCLC) viability and the detailed molecular mechanism involved are still unknown. Lung cancer remains a high-incidence, high-mortality malignancy, and approximately 85% are NSCLC, which including adenocarcinoma, bronchioloalveolar carcinoma, and squamous cell carcinoma. Most cases are already in an advanced stage when first diagnosed and thus cannot benefit from surgery. Platinum-based therapy remains the standard of care for the first-line treatment of patients with advanced NSCLC. On the other hand, gefitinib (IressaR) is selective epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) in the treatment of NSCLC, that blocks growth factor-mediated cell proliferation and extracellular signal-regulated kinases 1/2 (ERK1/2) signaling activation. Our previous studies have indicated that up-regulation of thymidine phosphorylase (TP), is an enzyme of the pyrimidine salvage pathway, expression is correlated decreasing drugs sensitivity of chemotherapeutic drug cisplatin to NSCLC cell lines. Interestingly, our preliminary results showed that metformin down-regulated the protein and mRNA expression of TP in a MKK1/2-ERK1/2 inactivation manner. Signal transducers and activators of transcription 3 (STAT3) inhibitors further decreased cellular tp mRNA expression in metformin-treated human lung cancer cells. Moreover, metformin synergistic enhances the chemotherapeutic drug doxorubicin-induced cytotoxic effects in breast cancer. However, the roles of TP in metformin enhancing cisplatin or gefitinib induced cytotoxic effect, proliferation inhibition, and mutagenesis in NSCLC is unclear. Therefore, first year, we will plan to explore how metformin inactivate MKK1/2-ERK1/2 signals and down-regulate TP expression in different types of NSCLC. Whether metformin decreased cellular TP expression was through the effect on transcription factor Sp1 and STAT3. Second year, we will determine whether metformin could directly or indirectly affect the catalytic activity of TP. How does metformin affect the chemotherapeutic drug (cisplatin) and EGFR-TKI (gefitinib) induced TP mRNA and protein expression? Could metformin enhance the sensitivity to cisplatin or gefitinib through increasing apoptosis, mutagenicity, and enhancing dNTP imbalance in NSCLC, due to decrease of the TP expression? The final goal of this project is to understand the how metformin modulate TP expression and its role in regulating metformin and chemotherapeutic drugs or EGFR-TKIs induced synergistic cytotoxicity in NSCLC cell lines. The findings prompt prospective investigations using metformin combined with chemotherapeutic drugs or EGFR-TKIs to optimize and improve clinical outcomes in lung cancer treatment. The clinical safety, well characterized pharmacodynamic profile, and low cost of metformin make it an ideal candidate for development as an anticancer agent for NSCLC. In conclusion, suppression of TP expression by metformin maybe a novel therapeutic modality in overcoming drug resistance of chemotherapeutic drugs or EGFR-TKIs in NSCLC.