Metformin Triggers Autophagy to Attenuate Drug-Induced Apoptosis in NSCLC Cells, with Minor Effects on Tumors of Diabetic Patients

Abstract

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.

Metformin upregulates mitophagy in patients with T2DM: A randomized placebo‐controlled study

“…It is well known that impaired mitophagy leads to the accelerated progression of mitochondrial dysfunction, which has been implicated in the aggravation of insulin resistance and deterioration of β‐cell function in patients with T2DM . Metformin is recommended as the first‐line drug in the management of T2DM, and its effect on autophagy is well explored; however, there is a dearth of literature regarding its impact on mitophagy . Furthermore, voglibose, an alpha‐glucosidase inhibitor, which neither has a direct effect on insulin sensitivity nor acts as a β‐cell secretagogue, was employed as an active comparator against metformin to eliminate the confounding influence of reduced glucotoxicity on mitochondrial health…”

Macroautophagy and Chaperone‐Mediated Autophagy in Heart Failure: The Known and the Unknown

“…It blocks phosphorylation of all mTORC1 substrates and is a more potent inducer of macroautophagy compared to rapamycin. Other pharmacological activators include Metformin, and a fusion peptide, Tat-Beclin 1, which was shown to activate macroautophagy [ 137 , 138 ]. Metformin activates macroautophagy by the phosphorylation and activation of AMPK [ 139 ].…”

Nephroprotection and chemotherapy sensitivity impact of metformin during cisplatin therapy; an updated review

“…These findings suggest that cisplatininduced AMPK activation and also mTOR pathway inhibition may lead to autophagy that defends cancer cells from cisplatin-induced cell death (27). However, findings a retrospective study also proposed that patients with lung cancer did not improve from metformin treatment due to increasing the expression of ERK1/2, AKT, and c-poly (ADP-ribose) polymerase (c-PARP) (28).…”