Dataset Information

Metformin inhibits growth and enhances radiation response of non-small cell lung cancer (NSCLC) through ATM and AMPK.

ABSTRACT:

Background

We examined the potential of metformin (MET) to enhance non-small cell lung cancer (NSCLC) responses to ionising radiation (IR).

Methods

Human NSCLC cells, mouse embryonic fibroblasts from wild-type and AMP-activated kinase (AMPK) ?1/2-subunit(-/-) embryos (AMPK?1/2(-/-)-MEFs) and NSCLC tumours grafted into Balb/c-nude mice were treated with IR and MET and subjected to proliferation, clonogenic, immunoblotting, cell cycle and apoptosis assays and immunohistochemistry (IHC).

Results

Metformin (2.5 ?M-5 mM) inhibited proliferation and radio-sensitised NSCLC cells. Metformin (i) activated the ataxia telengiectasia-mutated (ATM)-AMPK-p53/p21(cip1) and inhibited the Akt-mammalian target of rapamycin (mTOR)-eIF4E-binding protein 1 (4EBP1) pathways, (ii) induced G1 cycle arrest and (iii) enhanced apoptosis. ATM inhibition blocked MET and IR activation of AMPK. Non-small cell lung cancer cells with inhibited AMPK and AMPK?1/2(-/-)-MEFs were resistant to the antiproliferative effects of MET and IR. Metformin or IR inhibited xenograft growth and combined treatment enhanced it further than each treatment alone. Ionising radiation and MET induced (i) sustained activation of ATM-AMPK-p53/p21(cip1) and inhibition of Akt-mTOR-4EBP1 pathways in tumours, (ii) reduced expression of angiogenesis and (iii) enhanced expression of apoptosis markers.

Conclusion

Clinically achievable MET doses inhibit NSCLC cell and tumour growth and sensitise them to IR. Metformin and IR mediate their action through an ATM-AMPK-dependent pathway. Our results suggest that MET can be a clinically useful adjunct to radiotherapy in NSCLC.

SUBMITTER: Storozhuk Y

PROVIDER: S-EPMC3670487 | biostudies-literature | 2013 May

REPOSITORIES: biostudies-literature

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Publications

Metformin inhibits growth and enhances radiation response of non-small cell lung cancer (NSCLC) through ATM and AMPK.

Storozhuk Y Y Hopmans S N SN Sanli T T Barron C C Tsiani E E Cutz J-C JC Pond G G Wright J J Singh G G Tsakiridis T T

British journal of cancer 20130430 10

<h4>Background</h4>We examined the potential of metformin (MET) to enhance non-small cell lung cancer (NSCLC) responses to ionising radiation (IR).<h4>Methods</h4>Human NSCLC cells, mouse embryonic fibroblasts from wild-type and AMP-activated kinase (AMPK) α1/2-subunit(-/-) embryos (AMPKα1/2(-/-)-MEFs) and NSCLC tumours grafted into Balb/c-nude mice were treated with IR and MET and subjected to proliferation, clonogenic, immunoblotting, cell cycle and apoptosis assays and immunohistochemistry (I ...[more]

PMID: 23632475

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Dataset Information

Metformin inhibits growth and enhances radiation response of non-small cell lung cancer (NSCLC) through ATM and AMPK.

Background

Methods

Results

Conclusion

Publications

Metformin inhibits growth and enhances radiation response of non-small cell lung cancer (NSCLC) through ATM and AMPK.

Similar Datasets

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