Metformin Triggers Autophagy to Attenuate Drug-Induced Apoptosis in NSCLC Cells, with Minor Effects on Tumors of Diabetic Patients
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...
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| Format: | Article |
| Language: | English |
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Elsevier
2017-05-01
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| Series: | Neoplasia: An International Journal for Oncology Research |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S1476558617300489 |
| _version_ | 1811310793333932032 |
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| author | Zhiguang Xiao Silvia Gaertner Alicia Morresi-Hauf Rebecca Genzel Thomas Duell Axel Ullrich Pjotr G. Knyazev |
| author_facet | Zhiguang Xiao Silvia Gaertner Alicia Morresi-Hauf Rebecca Genzel Thomas Duell Axel Ullrich Pjotr G. Knyazev |
| author_sort | Zhiguang Xiao |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-13T10:05:28Z |
| format | Article |
| id | doaj.art-55d8786ed1624bb88a2325370860b226 |
| institution | Directory Open Access Journal |
| issn | 1476-5586 1522-8002 |
| language | English |
| last_indexed | 2024-04-13T10:05:28Z |
| publishDate | 2017-05-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Neoplasia: An International Journal for Oncology Research |
| spelling | doaj.art-55d8786ed1624bb88a2325370860b2262022-12-22T02:51:07ZengElsevierNeoplasia: An International Journal for Oncology Research1476-55861522-80022017-05-0119538539510.1016/j.neo.2017.02.011Metformin Triggers Autophagy to Attenuate Drug-Induced Apoptosis in NSCLC Cells, with Minor Effects on Tumors of Diabetic PatientsZhiguang Xiao0Silvia Gaertner1Alicia Morresi-Hauf2Rebecca Genzel3Thomas Duell4Axel Ullrich5Pjotr G. Knyazev6Department of Molecular Biology, Max-Planck-Institute of Biochemistry, Am Klopferspitz 18a, Martinsried, D-82152, GermanyDepartment of Molecular Biology, Max-Planck-Institute of Biochemistry, Am Klopferspitz 18a, Martinsried, D-82152, GermanyAsklepios Institute of Pathology, Munich-Gauting, Robert-Koch Alee, 2, D-82131, GermanyAsklepios Lung Clinic, Munich-Gauting, Robert-Koch Alee, 2; D-82131, GermanyAsklepios Lung Clinic, Munich-Gauting, Robert-Koch Alee, 2; D-82131, GermanyDepartment of Molecular Biology, Max-Planck-Institute of Biochemistry, Am Klopferspitz 18a, Martinsried, D-82152, GermanyDepartment of Molecular Biology, Max-Planck-Institute of Biochemistry, Am Klopferspitz 18a, Martinsried, D-82152, GermanyThe 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.http://www.sciencedirect.com/science/article/pii/S1476558617300489 |
| spellingShingle | Zhiguang Xiao Silvia Gaertner Alicia Morresi-Hauf Rebecca Genzel Thomas Duell Axel Ullrich Pjotr G. Knyazev Metformin Triggers Autophagy to Attenuate Drug-Induced Apoptosis in NSCLC Cells, with Minor Effects on Tumors of Diabetic Patients Neoplasia: An International Journal for Oncology Research |
| title | Metformin Triggers Autophagy to Attenuate Drug-Induced Apoptosis in NSCLC Cells, with Minor Effects on Tumors of Diabetic Patients |
| title_full | Metformin Triggers Autophagy to Attenuate Drug-Induced Apoptosis in NSCLC Cells, with Minor Effects on Tumors of Diabetic Patients |
| title_fullStr | Metformin Triggers Autophagy to Attenuate Drug-Induced Apoptosis in NSCLC Cells, with Minor Effects on Tumors of Diabetic Patients |
| title_full_unstemmed | Metformin Triggers Autophagy to Attenuate Drug-Induced Apoptosis in NSCLC Cells, with Minor Effects on Tumors of Diabetic Patients |
| title_short | Metformin Triggers Autophagy to Attenuate Drug-Induced Apoptosis in NSCLC Cells, with Minor Effects on Tumors of Diabetic Patients |
| title_sort | metformin triggers autophagy to attenuate drug induced apoptosis in nsclc cells with minor effects on tumors of diabetic patients |
| url | http://www.sciencedirect.com/science/article/pii/S1476558617300489 |
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