Metformin restores crizotinib sensitivity in crizotinib-resistant human lung cancer cells through inhibition of IGF1-R signaling pathway

Li, Li; Wang, Yübo; Peng, Tao; Zhang, Kejun; Lin, Caiyu; Han, Rui; Lu, Conghua; He, Yong

doi:10.18632/oncotarget.9120

Cited by 40 publications

(32 citation statements)

References 35 publications

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“…IGF‐1R signalling also mediates resistance to EGFR inhibition by TKIs and metformin has been shown to sensitize NSCLC cells that are resistant to EGFR‐inhibiting TKIs . For example, metformin restores crizotinib sensitivity in crizotinib‐resistant human lung cancer cells through inhibition of the IGF‐1R signalling pathway . Metformin has also been reported to reduce temozolomide resistance in glioblastoma cell lines .…”

Section: Resultsmentioning

confidence: 99%

“…35 For example, metformin restores crizotinib sensitivity in crizotinib-resistant human lung cancer cells through inhibition of the IGF-1R signalling pathway. 36 Metformin has also been reported to reduce temozolomide resistance in glioblastoma cell lines. 37 Paradoxically, a number of TKIs and mTOR inhibitors used in oncology are associated with drug-induced hyperglycaemia.…”

Section: Potential Use In Oncologymentioning

confidence: 99%

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Repurposing old drugs in oncology: Opportunities with clinical and regulatory challenges ahead

Shah

Stonier

2018

J Clin Pharm Ther

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Section: Resultsmentioning

confidence: 99%

Section: Potential Use In Oncologymentioning

confidence: 99%

Repurposing old drugs in oncology: Opportunities with clinical and regulatory challenges ahead

Shah

Stonier

2018

J Clin Pharm Ther

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“…Moreover, metformin treatment significantly improved the survival of lung cancer patients with epidermal growth factor receptor (EGFR)activating mutations and type 2 diabetes 15 . We also showed that metformin restores crizotinib sensitivity in crizotinibresistant NSCLC cells through the inhibition of the insulinlike growth factor 1 receptor (IGF1-R) signalling pathway 16 . It is worth noting that our previous study found that metformin exerted an inhibitory effect on downstream signalling mediators of MET, such as AKT and ERK 14 , which encouraged us to investigate whether metformin could restore alectinib sensitivity in alectinib-resistant cells with high expression of HGF and MET.…”

Section: Introductionmentioning

confidence: 89%

“…2b). According to the results of our previous study 16 , the in vitro dose of metformin used in this study was 5 mmol/L, which has minimal influence on ALKpositive NSCLC cell growth. Next, we performed the Ki67-incorporation assay and/or the colony-forming assay in H3122/Vec, H3122/HGF, and H3122-AR3 cells.…”

Section: Metformin Reverses the Alectinib Resistance Induced By Hgf/mmentioning

confidence: 98%

Metformin reduces HGF-induced resistance to alectinib via the inhibition of Gab1

et al. 2020

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Alectinib is a second-generation anaplastic lymphoma kinase (ALK) inhibitor that has sufficient clinical efficacy and satisfactory safety in ALK-positive non-small cell lung cancer (NSCLC) patients with or without brain metastasis. Alectinib has now become an important drug in the first-line treatment of advanced ALK-positive NSCLC; however, resistance is almost inevitable. The increased expression of hepatocyte growth factor (HGF) and its physiological receptor tyrosine kinase MET have been shown to be linked to acquired resistance to various tyrosine kinase inhibitors (TKIs), and this phenomenon has been observed in some ALK-positive NSCLC tumour tissues. In this study, we found that HGF levels in the culture supernatant of an ALK-positive cell line tended to increase with time and could be further increased by alectinib in a time-dependent manner. Exogenous or endogenous HGF did not cause resistance to the ALK/MET double-targeted small molecule inhibitor crizotinib, but it was an important cause of alectinib resistance. Furthermore, Gab1 was a key effector in the HGF/MET signal transduction pathway that mediated alectinib resistance. The antidiabetic drug metformin combined with alectinib overcame alectinib resistance triggered by HGF/ MET through disrupting the complex between MET and Gab1, thereby inhibiting Gab1 phosphorylation and the activation of downstream signal transduction pathways. These results suggest that metformin combined with alectinib may be useful for overcoming alectinib resistance induced by the activation of the HGF/MET signalling pathway and improving the efficacy of alectinib.

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“…22 Moreover, metformin can reverse crizotinib resistance by inhibiting type I insulin-like growth factor receptor (IGF-1R) signalling in crizotinib-resistant human lung cancer cells. 23 Metformin and sorafenib can synergistically inhibit tumour growth by activating the AMPK pathway in NSCLC cells both in vitro and in vivo. 24 Thus, combination of metformin with other chemotherapy agents may improve treatment outcome for NSCLC patients.…”

Section: Introductionmentioning

confidence: 99%

Metformin and tenovin‐6 synergistically induces apoptosis through LKB1‐independent SIRT1 down‐regulation in non‐small cell lung cancer cells

Lee

Kim

et al. 2019

J Cellular Molecular Medi

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Sirtuin 1 (SIRT1) is known to play a role in a variety of tumorigenesis processes by deacetylating histone and non‐histone proteins; however, antitumour effects by suppressing SIRT1 activity in non‐small cell lung cancer (NSCLC) remain unclear. This study was designed to scrutinize clinicopathological significance of SIRT1 in NSCLC and investigate effects of metformin on SIRT1 inhibition. This study also evaluated new possibilities of drug combination using a SIRT1 inhibitor, tenovin‐6, in NSCLC cell lines. It was found that SIRT1 was overexpressed in 300 (62%) of 485 formalin‐fixed paraffin‐embedded NSCLC tissues. Its overexpression was significantly associated with reduced overall survival and poor recurrence‐free survival after adjusted for histology and pathologic stage. Thus, suppression of SIRT1 expression may be a reasonable therapeutic strategy for NSCLC. Metformin in combination with tenovin‐6 was found to be more effective in inhibiting cell growth than either agent alone in NSCLC cell lines with different liver kinase B1 (LKB1) status. In addition, metformin and tenovin‐6 synergistically suppressed SIRT1 expression in NSCLC cells regardless of LKB1 status. The marked reduction in SIRT1 expression by combination of metformin and tenovin‐6 increased acetylation of p53 at lysine 382 and enhanced p53 stability in LKB1‐deficient A549 cells. The combination suppressed SIRT1 promoter activity more effectively than either agent alone by up‐regulating hypermethylation in cancer 1 (HIC1) binding at SIRT1 promoter. Also, suppressed SIRT1 expression by the combination synergistically induced caspase‐3‐dependent apoptosis. The study concluded that metformin with tenovin‐6 may enhance antitumour effects through LKB1‐independent SIRT1 down‐regulation in NSCLC cells.

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Metformin restores crizotinib sensitivity in crizotinib-resistant human lung cancer cells through inhibition of IGF1-R signaling pathway

Cited by 40 publications

References 35 publications

Repurposing old drugs in oncology: Opportunities with clinical and regulatory challenges ahead

Repurposing old drugs in oncology: Opportunities with clinical and regulatory challenges ahead

Metformin reduces HGF-induced resistance to alectinib via the inhibition of Gab1

Metformin and tenovin‐6 synergistically induces apoptosis through LKB1‐independent SIRT1 down‐regulation in non‐small cell lung cancer cells

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