Metformin Triggers Autophagy to Attenuate Drug-Induced Apoptosis in NSCLC Cells, with Minor Effects on Tumors of Diabetic Patients
| Autor: | Thomas Duell, Rebecca Genzel, Alicia Morresi-Hauf, Pjotr Knyazev, Zhiguang Xiao, Axel Ullrich, Silvia Gaertner |
|---|---|
| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Original article Cancer Research endocrine system diseases medicine.medical_treatment Poly (ADP-Ribose) Polymerase-1 Apoptosis Pharmacology medicine.disease_cause lcsh:RC254-282 Targeted therapy Erlotinib Hydrochloride Mice 03 medical and health sciences 0302 clinical medicine Carcinoma Non-Small-Cell Lung Cell Line Tumor Autophagy Animals Humans Medicine Lung cancer business.industry nutritional and metabolic diseases lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens medicine.disease Xenograft Model Antitumor Assays Metformin Neoplasm Proteins respiratory tract diseases ErbB Receptors 030104 developmental biology Diabetes Mellitus Type 2 030220 oncology & carcinogenesis Cancer cell Cancer research KRAS Erlotinib business Ovarian cancer medicine.drug |
| Zdroj: | Neoplasia (New York, N.Y.) Neoplasia: An International Journal for Oncology Research, Vol 19, Iss 5, Pp 385-395 (2017) Neoplasia |
| ISSN: | 1476-5586 |
| DOI: | 10.1016/j.neo.2017.02.011 |
| Popis: | The biologic plausibility of an association between type 2 diabetes mellitus (T2D) and lung cancer has received increasing attention, but the results of investigations remain largely inconclusive. In the present study we investigated the influence of the anti-diabetic drug metformin on the cytotoxic effects of EGFR targeted therapy and chemotherapy in 7 non-small cell lung cancer (NSCLC) cell lines and a cohort of lung cancer patients with/without T2D. In vitro cell viability assays indicated that metformin didn't potentiate the growth inhibitory effects of erlotinib at different doses in cell lines that are of distinct genetic background. EGFR downstream signaling evaluation further demonstrated that metformin, at its IC50 value, modified apoptosis caused in erlotinib or chemotherapeutic agent-treated cells via AKT activation and the inhibition of caspase 3 and PARP cleavages. These regulations were driven independently from EGFR, LKB1, KRAS, PTEN and p53 status. Metformin triggered autophagy (LC3B expression) was identified to interplay with apoptosis to attenuate the drug effect and postpone cancer cell death. In the retrospective study of 8 NSCLC patients, the administration of metformin did not induce statistically significant changes as assessed by immunohistochemical staining of pERK, pAKT and cleaved PARP. Consequently, the application of metformin for T2D NSCLC patients receiving chemo or EGFR targeted therapy should be considered with caution. |
| Databáze: | OpenAIRE |
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