Vorinostat and metformin sensitize EGFR-TKI resistant NSCLC cells via BIM-dependent apoptosis induction

Abstract

There is a close relationship between low expression of BIM and resistance to epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI). Vorinostat is a pan-histone deacetylase inhibitor (HDACi) that augments BIM expression in various types of tumor cells, however, this effect is attenuated by the high expression of anti-apoptotic proteins in EGFR-TKI resistant non-small cell lung cancer (NSCLC) cells. Vorinostat in combination with metformin – a compound that can inhibit anti-apoptotic proteins expression, might cooperate to activate apoptotic signaling and overcome EGFR-TKI resistance. This study aimed to investigate the cooperative effect and evaluate possible molecular mechanisms. The results showed that vorinostat combined with gefitinib augmented BIM expression and increased the sensitivity of EGFR-TKI resistant NSCLC cells to gefitinib, adding metformin simultaneously could obviously inhibit the expression of anti-apoptotic proteins, and further increased expression levels of BIM and BAX, and as a result, further improved the sensitivity of gefitinib both on the NSCLC cells with intrinsic and acquired resistance to EGFR-TKI. In addition, autophagy induced by gefitinib and vorinostat could be significantly suppressed by metformin, which might also contribute to enhance apoptosis and improve sensitivity of gefitinib. These results suggested that the combination of vorinostat and metformin might represent a novel strategy to overcome EGFR-TKI resistance associated with BIM-dependent apoptosis in larger heterogeneous populations.

Metformin‐sensitized NSCLC cells to osimertinib via AMPK‐dependent autophagy inhibition

“…Numerous investigations have provided evidence implying a potential role for metformin in cancer treatment, and some also showed that metformin influences autophagy in many kinds of tumour cell lines, and it affects different types of cancer cells in different ways. As the previous study showed, metformin inhibited autophagy induced by gefitinib and vorinostat whose mechanism had not been clear; in this research, the same phenomenon was observed in osimertinib‐treated NSCLC cells, and metformin combined with osimertinib had a synergistic anti‐tumour effect. Studies have found that the effective mechanism of metformin in cancer cells may be due to cell cycle arrest induction, mTOR inhibition, JAK2/STAT signalling inhibition, immunomodulation, cytotoxic properties and autophagy regulation .…”

Pleiotropic Effects of Metformin on Cancer

“…In a panel of non-small cell lung cancer (NSCLC) cell lines, MTF combined with an anti-IGF1R antibody inhibited IGF1R signaling and the combination of both MTF and anti-IGF1R antibody exerted additive inhibitory effects on cell viability [ 109 ]. In NSCLC cell lines that were resistant to EGFR tyrosine kinase inhibitors (TKIs), treatment with the pan-histone deacetylase inhibitor vorinostat and MTF synergistically improved sensitivity to the EGFR-TKI gefitinib [ 110 ]. Sensitivity was mediated by pro-apoptotic protein BCL2 like 11 (BCL2L11; alias, BIM) that induced apoptosis, whereas autophagy was significantly reduced by MTF.…”

Novel application of metformin combined with targeted drugs on anticancer treatment

“…Adding metformin to gefitinib reduced proliferation and the anchorage‐independent colony‐forming ability of a panel of NSCLC cell lines . Chen et al found that metformin clearly inhibited antiapoptotic protein expression, increased BIM and BAX, leading to significantly improved sensitivity of gefitinib. It has been reported that metformin can revert resistance to gefitinib .…”

“…Chen et al found that metformin clearly inhibited antiapoptotic protein expression, increased BIM and BAX, leading to significantly improved sensitivity of gefitinib. It has been reported that metformin can revert resistance to gefitinib . In xenografts with gefitinib‐resistant cancer cells, metformin blocked tumor growth and suppressed tumor relapse effectively.…”

“…It has been reported that metformin can revert resistance to gefitinib. 16,17 In xenografts with gefitinib-resistant cancer cells, metformin blocked tumor growth and suppressed tumor relapse effectively. A study from Ko et al showed that metformin augmented the cytotoxic effect and growth inhibition of gefitinib in human squamous lung cancer cells through decreasing MSH2 expression, which plays a central role in promoting genetic stability by correcting DNA replication errors.…”