Molecular mechanisms underlining the role of metformin as a therapeutic agent in lung cancer

Hassanabad, Ali Fatehi; MacQueen, Kelsey T

doi:10.1007/s13402-020-00570-0

Cited by 19 publications

(15 citation statements)

References 77 publications

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“…Previous literature has reviewed the scope of the potential antitumor effect of the use of metformin alone or as an adjuvant to other anticancer modalities, including chemotherapeutic reagents ( Peng et al, 2017 ; Levy and Doyen, 2018 ; Fatehi Hassanabad and MacQueen, 2020 ). Activation of the AMPK-dependent pathway has been extensively discussed ( Zakikhani et al, 2006 ; Emami Riedmaier et al, 2013 ; Sinnett-Smith et al, 2013 ).…”

Section: Discussionmentioning

confidence: 99%

“…Dosage and time dependent effects have been extensively shown. In preclinical studies, metformin demonstrates additive effects when combined with antitumor reagents and can overcome drug resistance and reduce chemotherapeutic dosages ( Kato et al, 2012 ; Lin et al, 2013 ; Tseng et al, 2013 ; Fatehi Hassanabad and MacQueen, 2020 ).…”

Section: Introductionmentioning

confidence: 99%

“…Targeting the mTOR pathway halts cell proliferation and growth. When metformin is used alone or combined with chemotherapeutic agents, more theories have been proposed ( Peng et al, 2017 ; Levy and Doyen, 2018 ; Fatehi Hassanabad and MacQueen, 2020 ). Luo et al (2019) found that metformin induces apoptosis by promoting survivin degradation through the AMPK/PKA (protein kinase A)/GSK (glycogen synthase kinase)-3B pathway in NSCLC.…”

Section: Introductionmentioning

confidence: 99%

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Additive Antiproliferative and Antiangiogenic Effects of Metformin and Pemetrexed in a Non-Small-Cell Lung Cancer Xenograft Model

Wang

Lan

Tsai

et al. 2021

Front. Cell Dev. Biol.

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Lung cancer is heterogeneous and challenging to cope with once it has progressed. Chemotherapy is the first step once no active driver mutation has been discovered. Non-antitumor drugs have been found to be beneficial when used as adjuvants to chemotherapy. In this study, the additive effect and mechanism of metformin combined with pemetrexed in non-small-cell lung cancer (NSCLC) cells were elucidated. Three NSCLC cell lines, A549, H1975, and HCC827, were used to analyze tumor cell proliferation, colony formation and the cell cycle in vitro when exposed to metformin alone, pemetrexed alone or their combination. We found that combination treatment in three cell lines exerted antiproliferative effects through cell cycle arrest in the S phase. An ex vivo chicken chorioallantoic membrane (CAM) assay was used to examine the antiangiogenic effect of metformin combined with pemetrexed on vascular structure formation. We further created an A549 orthotopic xenograft model with an in vivo imaging system (IVIS) and explored the associated indicators involved in the tumorigenic process. The in vitro results showed that the combination of metformin and pemetrexed exhibited an antiproliferative effect in reducing cell viability and colony formation, the downregulation of cyclin D1 and A2 and the upregulation of CDKN1B, which are involved in the G1/S phase. For antiangiogenic effects, the combination therapy inhibited the vascular structure, as proven by the CAM assay. We elucidated that combination therapy could target VEGFA and Endoglin by RT-qPCR, ELISA and histopathological findings in an A549 orthotopic NSCLC xenograft model. Our research demonstrated the additive antiproliferative and antiangiogenic effects of the combination of metformin with pemetrexed in NSCLC and could be applied to clinical lung cancer therapy.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Additive Antiproliferative and Antiangiogenic Effects of Metformin and Pemetrexed in a Non-Small-Cell Lung Cancer Xenograft Model

Wang

Lan

Tsai

et al. 2021

Front. Cell Dev. Biol.

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“…As these drugs are already used in clinical settings, drug repositioning would offer an efficient method to address the urgent need for the pharmacological treatment of P-gp overexpressing drug-resistant cancer, allowing the approval of the treatment relatively rapidly. For example, metformin, a wellknown drug used to treat type 2 diabetes mellitus, has anticancer effects and is clinically widely tested as a repositioned drug (3)(4)(5)(6)(7).…”

Section: Fda-approved Drug Repositioning For P-glycoprotein Overexprementioning

confidence: 99%

Editorial: FDA-Approved Drug Repositioning for P-Glycoprotein Overexpressing Resistant Cancer

et al. 2021

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“…Metformin has also been reported to prevent fibrosis in several organs, including the kidneys [18,19]. In addition to treatment of diabetes, the drug has also been reported to be beneficial in treating several other diseases and conditions that include lung and breast cancers [20,21], inflammatory skin disorders [22], and neurological diseases [23].…”

Section: Introductionmentioning

confidence: 99%

The Effect of Metformin in Diabetic and Non-Diabetic Rats with Experimentally-Induced Chronic Kidney Disease

et al. 2021

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This work aimed to investigate whether treatment with the antidiabetic drug metformin would affect adenine-induced chronic kidney disease (CKD) in non-diabetic rats and rats with streptozotocin (STZ)-induced diabetes. Rats were randomly divided into eight groups, and given either normal feed, or feed mixed with adenine (0.25% w/w, for five weeks) to induce CKD. Some of these groups were also simultaneously treated orally with metformin (200 mg/kg/day). Rats given adenine showed the typical signs of CKD that included detrimental changes in several physiological and traditional and novel biochemical biomarkers in plasma urine and kidney homogenates such as albumin/creatinine ratio, N-acetyl-beta-D-glucosaminidase, neutrophil gelatinase-associated lipocalin, 8-isoprostane, adiponectin, cystatin C, as well as plasma urea, creatinine, uric acid, indoxyl sulfate, calcium, and phosphorus. Several indices of inflammation and oxidative stress, and renal nuclear factor-κB and nuclear factor erythroid 2-related factor 2 levels were also measured. Histopathologically, adenine caused renal tubular necrosis and fibrosis. The activation of the intracellular mitogen-activated protein kinase signaling pathway was inhibited in the groups that received metformin and STZ together, with or without adenine induced-CKD. Induction of diabetes worsened most of the actions induced by adenine. Metformin significantly ameliorated the renal actions induced by adenine and STZ when these were given singly, and more so when given together. The results suggest that metformin can be a useful drug in attenuating the progression of CKD in both diabetic and non-diabetic rats.

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Molecular mechanisms underlining the role of metformin as a therapeutic agent in lung cancer

Cited by 19 publications

References 77 publications

Additive Antiproliferative and Antiangiogenic Effects of Metformin and Pemetrexed in a Non-Small-Cell Lung Cancer Xenograft Model

Additive Antiproliferative and Antiangiogenic Effects of Metformin and Pemetrexed in a Non-Small-Cell Lung Cancer Xenograft Model

Editorial: FDA-Approved Drug Repositioning for P-Glycoprotein Overexpressing Resistant Cancer

The Effect of Metformin in Diabetic and Non-Diabetic Rats with Experimentally-Induced Chronic Kidney Disease

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