The Clinical Effect of Metformin on the Survival of Lung Cancer Patients with Diabetes: A Comprehensive Systematic Review and Meta-analysis of Retrospective Studies

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Abstract

Preclinical investigations have revealed an anti-cancer effect of metformin. Several studies of metformin treatment have demonstrated the improved clinical outcomes of lung cancer patients with diabetes; however, the results have been inconsistent among studies. Our systematic review and meta-analysis aimed to summarize the up-to-date effects of metformin on diabetic lung cancer patients.

A systematic search was performed for studies published. Then, these studies were evaluated for inclusion, and relevant data was extracted. The summary risk estimates for the associations of metformin treatment with overall survival (OS) and progression-free survival (PFS) were analyzed using random/fixed-effects models. Analyses stratified by histological type were also conducted. Based on the 10 studies included in our analysis, metformin treatment was found to significantly improve survival, corresponding to reductions of 23% and 47% in OS [hazard ratio (HR)=0.77, 95% confidence interval (95%CI)=0.66-0.9, p=0.001] and PFS (HR=0.53, 95%CI=0.41-0.68, p<0.001), respectively. In addition, significant improvements in the OS for non-small cell lung cancer (NSCLC) (HR=0.77, 95%CI=0.71-0.84, p=0.002) and small cell lung cancer (SCLC) (HR=0.52, 95%CI=0.29-0.91, p=0.022) were observed in association with metformin treatment in analysis stratified by histological type. This stratified analysis also revealed a significant improvement in PFS for both NSCLC (HR=0.53, 95%CI=0.39-0.71, p<0.001) and SCLC (HR=0.54, 95%CI=0.34-0.84, p=0.007). We found that metformin treatment significantly improved the OS and PFS of diabetic lung cancer patients, and our findings suggest that metformin might be an effective treatment option for diabetic patients with lung cancer.

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Metformin is an AMP kinase-dependent growth inhibitor for breast cancer cells.

Mahvash Zakikhani, Ryan Dowling, I. George Fantus … (2006)

Recent population studies provide clues that the use of metformin may be associated with reduced incidence and improved prognosis of certain cancers. This drug is widely used in the treatment of type 2 diabetes, where it is often referred to as an "insulin sensitizer" because it not only lowers blood glucose but also reduces the hyperinsulinemia associated with insulin resistance. As insulin and insulin-like growth factors stimulate proliferation of many normal and transformed cell types, agents that facilitate signaling through these receptors would be expected to enhance proliferation. We show here that metformin acts as a growth inhibitor rather than an insulin sensitizer for epithelial cells. Breast cancer cells can be protected against metformin-induced growth inhibition by small interfering RNA against AMP kinase. This shows that AMP kinase pathway activation by metformin, recently shown to be necessary for metformin inhibition of gluconeogenesis in hepatocytes, is also involved in metformin-induced growth inhibition of epithelial cells. The growth inhibition was associated with decreased mammalian target of rapamycin and S6 kinase activation and a general decrease in mRNA translation. These results provide evidence for a mechanism that may contribute to the antineoplastic effects of metformin suggested by recent population studies and justify further work to explore potential roles for activators of AMP kinase in cancer prevention and treatment.

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Insulin receptor isoforms and insulin receptor/insulin-like growth factor receptor hybrids in physiology and disease.

Antonino Belfiore, Francesco Frasca, Giuseppe Pandini … (2009)

In mammals, the insulin receptor (IR) gene has acquired an additional exon, exon 11. This exon may be skipped in a developmental and tissue-specific manner. The IR, therefore, occurs in two isoforms (exon 11 minus IR-A and exon 11 plus IR-B). The most relevant functional difference between these two isoforms is the high affinity of IR-A for IGF-II. IR-A is predominantly expressed during prenatal life. It enhances the effects of IGF-II during embryogenesis and fetal development. It is also significantly expressed in adult tissues, especially in the brain. Conversely, IR-B is predominantly expressed in adult, well-differentiated tissues, including the liver, where it enhances the metabolic effects of insulin. Dysregulation of IR splicing in insulin target tissues may occur in patients with insulin resistance; however, its role in type 2 diabetes is unclear. IR-A is often aberrantly expressed in cancer cells, thus increasing their responsiveness to IGF-II and to insulin and explaining the cancer-promoting effect of hyperinsulinemia observed in obese and type 2 diabetic patients. Aberrant IR-A expression may favor cancer resistance to both conventional and targeted therapies by a variety of mechanisms. Finally, IR isoforms form heterodimers, IR-A/IR-B, and hybrid IR/IGF-IR receptors (HR-A and HR-B). The functional characteristics of such hybrid receptors and their role in physiology, in diabetes, and in malignant cells are not yet fully understood. These receptors seem to enhance cell responsiveness to IGFs.

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Metformin inhibits mammalian target of rapamycin-dependent translation initiation in breast cancer cells.

Ryan J O Dowling, Mahvash Zakikhani, I. George Fantus … (2007)

Metformin is used for the treatment of type 2 diabetes because of its ability to lower blood glucose. The effects of metformin are explained by the activation of AMP-activated protein kinase (AMPK), which regulates cellular energy metabolism. Recently, we showed that metformin inhibits the growth of breast cancer cells through the activation of AMPK. Here, we show that metformin inhibits translation initiation. In MCF-7 breast cancer cells, metformin treatment led to a 30% decrease in global protein synthesis. Metformin caused a dose-dependent specific decrease in cap-dependent translation, with a maximal inhibition of 40%. Polysome profile analysis showed an inhibition of translation initiation as metformin treatment of MCF-7 cells led to a shift of mRNAs from heavy to light polysomes and a concomitant increase in the amount of 80S ribosomes. The decrease in translation caused by metformin was associated with mammalian target of rapamycin (mTOR) inhibition, and a decrease in the phosphorylation of S6 kinase, ribosomal protein S6, and eIF4E-binding protein 1. The effects of metformin on translation were mediated by AMPK, as treatment of cells with the AMPK inhibitor compound C prevented the inhibition of translation. Furthermore, translation in MDA-MB-231 cells, which lack the AMPK kinase LKB1, and in tuberous sclerosis complex 2 null (TSC2(-/-)) mouse embryonic fibroblasts was unaffected by metformin, indicating that LKB1 and TSC2 are involved in the mechanism of action of metformin. These results show that metformin-mediated AMPK activation leads to inhibition of mTOR and a reduction in translation initiation, thus providing a possible mechanism of action of metformin in the inhibition of cancer cell growth.

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Author and article information

Journal

Journal ID (nlm-ta): J Cancer

Journal ID (iso-abbrev): J Cancer

Journal ID (publisher-id): jca

Title: Journal of Cancer

Publisher: Ivyspring International Publisher (Sydney )

ISSN (Electronic): 1837-9664

Publication date Collection: 2017

Publication date (Electronic): 2 August 2017

Volume: 8

Issue: 13

Pages: 2532-2541

Affiliations

[1 ]Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Guangzhou, Guangdong, China;

[2 ]Department of Thoracic Oncology, Sun Yat-Sen University Cancer Center, Guangzhou, Guangdong, China.

Author notes

✉ Corresponding author: Dr. Xin Wang, MD, Department of Thoracic Oncology, Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, No. 651 Dong-Feng Road East, Guangzhou, Guangdong 510060, China. E-mail: caoxun@ 123456sysucc.org.cn (Xin Wang)

*Xun Cao and Zhe-Sheng Wen have contributed equally to this work.

Competing Interests: The authors have declared that no competing interest exists.

Article

Publisher ID: jcav08p2532

DOI: 10.7150/jca.19750

PMC ID: 5595083

PubMed ID: 28900491

SO-VID: 67d47f52-c34c-4173-93f4-6de9cce85aa2

License:

This is an open access article distributed under the terms of the Creative Commons Attribution (CC BY-NC) license ( https://creativecommons.org/licenses/by-nc/4.0/). See http://ivyspring.com/terms for full terms and conditions.

The Clinical Effect of Metformin on the Survival of Lung Cancer Patients with Diabetes: A Comprehensive Systematic Review and Meta-analysis of Retrospective Studies

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Most cited references 39

Metformin is an AMP kinase-dependent growth inhibitor for breast cancer cells.

Insulin receptor isoforms and insulin receptor/insulin-like growth factor receptor hybrids in physiology and disease.

Metformin inhibits mammalian target of rapamycin-dependent translation initiation in breast cancer cells.

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