Metformin Sensitizes EGFR-TKI–Resistant Human Lung Cancer Cells In Vitro and In Vivo through Inhibition of IL-6 Signaling and EMT Reversal

Abstract

Purpose: The EGF receptor tyrosine kinase inhibitors (EGFR-TKI) have become a standard therapy in patients with EGFR-activating mutations. Unfortunately, acquired resistance eventually limits the clinical effects and application of EGFR-TKIs. Studies have shown that suppression of epithelial-mesenchymal transition (EMT) and the interleukin (IL)-6/STAT3 pathway may abrogate this acquired mechanism of drug resistance of TKIs. This study aims to investigate the effect of metformin on sensitizing EGFR-TKI-resistant human lung cancer cells in vitro and in vivo through inhibition of IL-6 signaling and EMT reversal.Experimental Design: The effect of metformin on reversing TKI resistance was examined in vitro and in vivo using MTT, BrdUrd incorporation assay, invasion assay, flow cytometry analysis, immunostaining, Western blot analysis, and xenograft implantation.Results: In this study, metformin, a widely used antidiabetic agent, effectively increased the sensitivity of TKI-resistant lung cancer cells to erlotinib or gefitinib. Metformin reversed EMT and decreased IL-6 signaling activation in TKI-resistant cells, while adding IL-6 to those cells bypassed the anti-TKI-resistance effect of metformin. Furthermore, overexpression or addition of IL-6 to TKI-sensitive cells induced TKI resistance, which could be overcome by metformin. Finally, metformin-based combinatorial therapy effectively blocked tumor growth in xenografts with TKI-resistant cancer cells, which was associated with decreased IL-6 secretion and expression, EMT reversal, and decreased IL-6-signaling activation in vivo.Conclusion: Metformin, generally considered nontoxic and remarkably inexpensive, might be used in combination with TKIs in patients with non-small cell lung cancer, harboring EGFR mutations to overcome TKI resistance and prolong survival.

Polyphyllin I Overcomes EMT-Associated Resistance to Erlotinib in Lung Cancer Cells <i>via</i> IL-6/STAT3 Pathway Inhibition

“…42) Inhibiting IL-6/STAT3 pathway suppressed cancer cell proliferation and restored the sensitivity to TKI. 26,43) This suggests that the antagonism of IL-6/STAT3 pathway could be therapeutically beneficial for the treatment of drug-resistant tumors that are driven by EMT-like phenomena. 44) In this study, we observed the activation of IL-6/STAT3 signaling pathway in ER cells, elevated IL-6 promotes EMT through altered expression of N-cadherin, vimentin and E-cadherin leading to enhanced cancer invasion.…”

Pirfenidone may revert the epithelial-to-mesenchymal transition in human lung adenocarcinoma

“…Due to its roles in cancer invasion, metastasis and chemoresistance, the inhibition or reversion of the EMT has been regarded as a promising strategy for treating cancer. Several agents, including a mechanistic target of rapamycin inhibitor (6) and metformin (7), have been reported to suppress EMT in lung cancer. However, effective approaches for inhibiting the EMT have not been established.…”

Early, Goal-Directed Resuscitation for Septic Shock

“…To the Editor: The Protocolised Management in Sepsis (ProMISe) trial (April 2 issue) 1 completes a trio of studies [1][2][3] that question the further application of early, goal-directed therapy (EGDT) as suggested by Rivers et al 4 In particular, these trials consistently show no survival benefit with regard to the mandated use of central venous oxygen saturation (ScvO 2 ) monitoring. However, it remains questionable whether the results of the three trials support this claim.…”

“…These results strongly support the pivotal role of the SSC guidelines that include EGDT. [1][2][3] Although these trials reveal that monitoring of central venous pressure is not mandatory, they show no harm in EGDT and certainly do not suggest that other aspects of the guidelines be called into question. We are concerned that the conclusions promulgated by the triad of trials will be misinterpreted and will cast doubt on the importance of SSC protocols for sepsis detection and treatment.…”

“…2 Our study showed that metformin sensitizes NSCLC cells that are resistant to EGFR tyrosine kinase inhibitors. 3 Furthermore, metformin suppresses the expression of the main detoxification enzyme, cytochrome P-450 3A4. 4 Therefore, it could theoretically elevate plasma concentrations of rociletinib.…”