Pleiotropic Effects of Metformin on Cancer

Schulten, Hans-Juergen

doi:10.3390/ijms19102850

Cited by 65 publications

(66 citation statements)

References 177 publications

(193 reference statements)

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“…Primer sequence PCR product (bp) 21]. The epidemiologic data indicate that MET intake significantly enhances the clinical outcome of patients with ovarian cancer [22][23][24].…”

Section: Genementioning

confidence: 99%

Enhanced anti-proliferative and pro-apoptotic effects of metformin encapsulated PLGA-PEG nanoparticles on SKOV3 human ovarian carcinoma cells

Faramarzi

Dadashpour

Sadeghzadeh

et al. 2019

Artificial Cells, Nanomedicine, and Biotechnology

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Metformin (MET) has received considerable attention in recent years for its anticancer potential activities. However, short half-life and weak bioavailability of MET limited its use as a chemotherapeutic agent. The present study is intended to evaluate the efficiency of PLGA-PEG as a nano-carrier for MET to increase anticancer effects on SKOV3 ovarian carcinoma cells. MET-loaded PLGA-PEG nanoparticles (NPs) were characterized through Dynamic Light Scattering (DLS), Fourier-transform infrared spectroscopy (FTIR) and field emission scanning electron microscopy (FE-SEM). Anti-proliferative and apoptotic effects of nanoformulated MET were evaluated using MTT and flow-cytometric assays, respectively. Also, real-time polymerase chain reaction (Real-Time PCR) was used to determine the gene expression levels of apoptotic genes, p53 and hTERT. Evaluation of cytotoxicity showed that MET-NPs had more cytotoxicity than free MET in a time-and dose-dependent manner. The nuclei fragmentation and the percentage of apoptotic cells induced by MET-NPs were significantly higher than free MET. Also, it was found that MET-NPs triggered more cell cycle arrest at sub-G1 checkpoint than free MET. Compared to MET treated cells, the mRNA expression levels of apoptotic genes, as well as p53 and hTERT were significantly altered in MET-NPs treated cells. In conclusion, it is supposed that nano-encapsulation of MET into polymeric PLGA-PEG NPs may be a convenient drug delivery system to enhance its anticancer effects for ovarian cancer therapy.

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“…Primer sequence PCR product (bp) 21]. The epidemiologic data indicate that MET intake significantly enhances the clinical outcome of patients with ovarian cancer [22][23][24].…”

Section: Genementioning

confidence: 99%

Enhanced anti-proliferative and pro-apoptotic effects of metformin encapsulated PLGA-PEG nanoparticles on SKOV3 human ovarian carcinoma cells

Faramarzi

Dadashpour

Sadeghzadeh

et al. 2019

Artificial Cells, Nanomedicine, and Biotechnology

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“…The anti-cancer potential of metformin was first recognized in diabetic patients. These patients treated with metformin were characterized by a lower cancer incidence in comparison to patients who were on other anti-diabetic medications (Schulten 2018). Subsequently, several epidemiological data documented the association between metformin therapy and a lower risk of developing breast, colon, pancreatic and liver cancers in diabetic patients (Andrzejewski et al 2018).…”

Section: Introductionmentioning

confidence: 99%

The role of an anti-diabetic drug metformin in the treatment of endocrine tumors

Thakur

Daley

Kłubo-Gwieździńska

2019

Journal of Molecular Endocrinology

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Incidence of endocrine cancers is rising every year. Over the last decade, evidence has accumulated that demonstrates the anti-cancer effects of an anti-diabetic drug, metformin, in endocrine malignancies. We performed a literature review utilizing the PubMed, Medline and clinicaltrials.gov databases using the keyword ‘metformin’ plus the following terms: ‘thyroid cancer’, ‘thyroid nodules’, ‘parathyroid’, ‘hyperparathyroidism’, ‘adrenal adenoma’, ‘Cushing syndrome’, ‘hyperaldosteronism’, ‘adrenocortical cancer’, ‘neuroendocrine tumor (NET)’, ‘pancreatic NET (pNET)’, ‘carcinoid’, ‘pituitary adenoma’, ‘pituitary neuroendocrine tumor (PitNET)’, ‘prolactinoma’, ‘pheochromocytoma/paraganglioma’. We found 37 studies describing the preclinical and clinical role of metformin in endocrine tumors. The available epidemiological data show an association between exposure of metformin and lower incidence of thyroid cancer and pNETs in diabetic patients. Metformin treatment has been associated with better response to cancer therapy in thyroid cancer and pNETs. Preclinical evidence suggests that the primary direct mechanisms of metformin action include inhibition of mitochondrial oxidative phosphorylation via inhibition of both mitochondrial complex I and mitochondrial glycerophosphate dehydrogenase, leading to metabolic stress. Decreased ATP production leads to an activation of a cellular energy sensor, AMPK, and subsequent downregulation of mTOR signaling pathway, which is associated with decreased cellular proliferation. We also describe several AMPK-independent mechanisms of metformin action, as well as the indirect mechanisms targeting insulin resistance. Overall, repositioning of metformin has emerged as a promising strategy for adjuvant therapy of endocrine tumors. The mechanisms of synergy between metformin and other anti-cancer agents need to be elucidated further to guide well-designed prospective trials on combination therapies in endocrine malignancies.

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“…The only clear exception was metformin: DKO5 cells displayed resistance when exposed to this drug. Metformin has very diverse spectrum of interactions [28], including the ability to bind and transfer copper atoms [37], the latter may enhance the viability of copper deficient DKO5 cells. Being metformin widely used for different indication, including cancer, the knowledge that copper levels or transport can modify its activity could have, if confirmed important implications.…”

Section: Discussionmentioning

confidence: 99%

“…STF-31, specific glucose transporter inhibitor [27], showed a slightly reduced activity in CTR-1 KO cells and even less in DKO clone. Meanwhile, interesting results were obtained with the AMPK inhibitor metformin, which decreases blood glucose concentration and is widely used in the treatment of obesity and now largely in some types of cancer [28]. With this drug parental cells and the single KO (both CTR-1 and DMT-1) behaved similarly.…”

Section: Ctr1-ko Dmt1-ko and Dko Cells The Synthesis Of Immunoreactmentioning

confidence: 99%

CRISP-R/Cas9 Mediated Deletion of Copper Transport Genes CTR1 and DMT1 in NSCLC Cell Line H1299. Biological and Pharmacological Consequences

Ilyechova

Bonaldi

Orlov

et al. 2018

Preprint

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Copper, the highly toxicity micronutrient, plays two essential roles: it is a catalytic and structural cofactor for Cu-dependent enzymes, and it acts as a secondary messenger. In the cells, copper is imported by CTR1, a transmembrane high-affinity copper importer, and DMT1 (divalent metal transporter). In cytosol, enzyme-specific chaperones receive copper from CTR1 C-terminus and deliver it to their apoenzymes. DMT1 cannot be a donor of catalytic copper because it does not have cytosol domain which is required for copper transfer to the Cu-chaperons and following to cuproenzymes. Here we assume that DMT1 can mediate copper way required for regulatory copper pool. To verify this thought, we used CRISPR/Cas9 to generate H1299 cell line with CTR1 or DMT1 single knockout (KO) and CTR1/DMT1 double knockout (DKO). To confirm KOs of the genes qRT-PCR were used. Two independent clones for each gene were selected for further studies. In CTR1-KO cells, expression of the DMT1 gene was significantly increased. In subcellular compartments, copper concentration decreased dramatically in DKO cells. CTR1-KO cells, but not DMT1-KO, demonstrated reduced sensitivity to cisplatin and silver ions, agents that enter the cell through CTR1. The expression of genes, whose protein products require copper: HIF1α, XIAP, COMMD1, CCS, Cp, but not SOD1 and NF-kB, changed their level. Perhaps these data will help to understand how the disturbances of copper homeodynamics lead to the development of neurodegenerative and oncological disorders. Possibility of using CTR1 KO and DMT1 KO cells to study homeodynamics of catalytic and signaling copper selectively is discussed.

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Pleiotropic Effects of Metformin on Cancer

Cited by 65 publications

References 177 publications

Enhanced anti-proliferative and pro-apoptotic effects of metformin encapsulated PLGA-PEG nanoparticles on SKOV3 human ovarian carcinoma cells

Enhanced anti-proliferative and pro-apoptotic effects of metformin encapsulated PLGA-PEG nanoparticles on SKOV3 human ovarian carcinoma cells

The role of an anti-diabetic drug metformin in the treatment of endocrine tumors

CRISP-R/Cas9 Mediated Deletion of Copper Transport Genes CTR1 and DMT1 in NSCLC Cell Line H1299. Biological and Pharmacological Consequences

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