Metformin represses glucose starvation induced autophagic response in microvascular endothelial cells and promotes cell death

Samuel, Samson Mathews; Ghosh, Suparna; Majeed, Yasser; Arunachalam, Gnanapragasam; Emara, Mohamed M.; Ding, Hong; Triggle, Chris R.

doi:10.1016/j.bcp.2017.03.001

Cited by 35 publications

(65 citation statements)

References 69 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…On the other hand, metformin treatment in glucose-starved/deprived breast cancer cells induced cell death [139]. We have shown that the ability of metformin to inhibit the Akt/mTOR pathway, induce G 2 /M cell cycle arrest, and cell death in microvascular endothelial cells overexpressing VEGF, was enhanced under glucose-starved conditions [68,138]. This was shown to be true in other cancer cells as well [68,138].…”

Section: Cellular and Pre-clinical Datamentioning

confidence: 74%

“…We have shown that the ability of metformin to inhibit the Akt/mTOR pathway, induce G 2 /M cell cycle arrest, and cell death in microvascular endothelial cells overexpressing VEGF, was enhanced under glucose-starved conditions [68,138]. This was shown to be true in other cancer cells as well [68,138]. In MCF7, SKBR3, and MDA-MB-231 cells, metformin effectively activated AMPK dependent apoptosis (partially independent of mTORC1) at physiological glucose conditions while the efficacy of metformin was lost under high glucose or amino acid rich conditions [140].…”

Section: Cellular and Pre-clinical Datamentioning

confidence: 99%

“…Metformin also exhibited 'direct' anti-cancer effects in many different cancer related studies. Since cancer cells are known to utilize glucose rapidly through glycolysis (Warburg effect) to meet their energy needs when compared to normal cells, metformin-mediated decrease in glucose levels should also curb tumor growth, although reports suggest that cancer cells use alternative sources of energy when starved of glucose or when glycolysis is inhibited [45,[66][67][68]. Furthermore, AMPK inhibits IRS1 mediated IR and IGFR oncogenic signaling via PI3K/Akt/mTOR, which, potentially, also contributes to the anti-cancer effect of metformin ( Figure 2) [69][70][71].…”

Section: Biology Of Metformin and Molecular Mechanism Of Actionmentioning

confidence: 99%

“…Dosage of metformin administration as a monotherapy or in combination with other drugs or therapeutic modalities is critical to achieve therapeutic efficiency in the treatment with minimal side effects. When used orally in the treatment of diabetes, the anti-hyperglycemic effects of metformin have been reported at plasma concentrations ranging from around from 10-100 µM [68,137,203]. Interestingly, epidemiological, observational, and meta-analysis reports suggest that oral administration of metformin (normal initial oral dose for; 'immediate release' is 500 mg twice/day or 850 mg once/day, with 500 mg increments weekly as tolerated, maximum dose of 2550 mg/day; 'extended release' is 500 to 1000 mg once/day, with 500 mg increments weekly as tolerated, maximum dose of 2000 mg/day) in type 2 diabetic patients significantly reduced the risk of many different cancers when compared to diabetic patients on other anti-hyperglycemic treatment regimens [35,37,204,205].…”

Section: Mixed Messages and Challengesmentioning

confidence: 99%

See 3 more Smart Citations

Metformin: The Answer to Cancer in a Flower? Current Knowledge and Future Prospects of Metformin as an Anti-Cancer Agent in Breast Cancer

et al. 2019

View full text Add to dashboard Cite

Interest has grown in studying the possible use of well-known anti-diabetic drugs as anti-cancer agents individually or in combination with, frequently used, chemotherapeutic agents and/or radiation, owing to the fact that diabetes heightens the risk, incidence, and rapid progression of cancers, including breast cancer, in an individual. In this regard, metformin (1, 1-dimethylbiguanide), well known as ‘Glucophage’ among diabetics, was reported to be cancer preventive while also being a potent anti-proliferative and anti-cancer agent. While meta-analysis studies reported a lower risk and incidence of breast cancer among diabetic individuals on a metformin treatment regimen, several in vitro, pre-clinical, and clinical studies reported the efficacy of using metformin individually as an anti-cancer/anti-tumor agent or in combination with chemotherapeutic drugs or radiation in the treatment of different forms of breast cancer. However, unanswered questions remain with regards to areas such as cancer treatment specific therapeutic dosing of metformin, specificity to cancer cells at high concentrations, resistance to metformin therapy, efficacy of combinatory therapeutic approaches, post-therapeutic relapse of the disease, and efficacy in cancer prevention in non-diabetic individuals. In the current article, we discuss the biology of metformin and its molecular mechanism of action, the existing cellular, pre-clinical, and clinical studies that have tested the anti-tumor potential of metformin as a potential anti-cancer/anti-tumor agent in breast cancer therapy, and outline the future prospects and directions for a better understanding and re-purposing of metformin as an anti-cancer drug in the treatment of breast cancer.

show abstract

Section: Cellular and Pre-clinical Datamentioning

confidence: 74%

Section: Cellular and Pre-clinical Datamentioning

confidence: 99%

Section: Biology Of Metformin and Molecular Mechanism Of Actionmentioning

confidence: 99%

Section: Mixed Messages and Challengesmentioning

confidence: 99%

See 2 more Smart Citations

Metformin: The Answer to Cancer in a Flower? Current Knowledge and Future Prospects of Metformin as an Anti-Cancer Agent in Breast Cancer

et al. 2019

View full text Add to dashboard Cite

show abstract

“…SDS-Polyacrylamide Gel Electrophoresis (SDS-PAGE) was performed and followed by immuno-blotting to detect the levels of peIF2α (S51), eIF2α, NANOG, OCT4, LIN28, KLF4, SOX2, L1TD1, DPPA5 and β-ACTIN as previously described [41]. Briefly, cell lysate protein (15–30μg) was separated on an SDS-PAGE gel and trans-blotted onto nitrocellulose membranes, blocked with 5% (w/v) non-fat dry milk or bovine serum albumin in Tris-buffered saline (TBS) containing 0.1% (v/v) Tween 20 and incubated in the relevant primary antibody (1:1000 dilution), at 4°C on a rocking platform, overnight.…”

Section: Methodsmentioning

confidence: 99%

Effects of oxidative and thermal stresses on stress granule formation in human induced pluripotent stem cells

et al. 2017

Self Cite

View full text Add to dashboard Cite

Stress Granules (SGs) are dynamic ribonucleoprotein aggregates, which have been observed in cells subjected to environmental stresses, such as oxidative stress and heat shock (HS). Although pluripotent stem cells (PSCs) are highly sensitive to oxidative stress, the role of SGs in regulating PSC self-renewal and differentiation has not been fully elucidated. Here we found that sodium arsenite (SA) and HS, but not hydrogen peroxide (H2O2), induce SG formation in human induced (hi) PSCs. Particularly, we found that these granules contain the well-known SG proteins (G3BP, TIAR, eIF4E, eIF4A, eIF3B, eIF4G, and PABP), were found in juxtaposition to processing bodies (PBs), and were disassembled after the removal of the stress. Moreover, we showed that SA and HS, but not H2O2, promote eIF2α phosphorylation in hiPSCs forming SGs. Analysis of pluripotent protein expression showed that HS significantly reduced all tested markers (OCT4, SOX2, NANOG, KLF4, L1TD1, and LIN28A), while SA selectively reduced the expression levels of NANOG and L1TD1. Finally, in addition to LIN28A and L1TD1, we identified DPPA5 (pluripotent protein marker) as a novel component of SGs. Collectively, these results provide new insights into the molecular cues of hiPSCs responses to environmental insults.

show abstract

The protective role of metformin in autophagic status in peripheral blood mononuclear cells of type 2 diabetic patients

Bhattacharya¹,

Dutta²,

Mukhopadhyay³

et al. 2020

Cell Biology International

View full text Add to dashboard Cite

Autophagy plays an important role in the pathophysiology of type 2 diabetes (T2D). Metformin is the most common antidiabetic drug. The main objective of this study was to explore the molecular mechanism of metformin in starvation‐induced autophagy in peripheral blood mononuclear cells (PBMCs) of type 2 diabetic patients. PBMCs were isolated from 10 diabetic patients and 7 non‐diabetic healthy volunteers. The autophagic puncta and markers were measured with the help of monodansylcadaverine staining and western blot. Additionally, transmission electron microscopy was also performed. No significant changes were observed in the initial autophagy marker protein levels in PBMCs of T2D after metformin treatment though diabetic PBMCs showed a high level of phospho‐mammalian target of rapamycin, p62 and reduced expression of phospho‐AMP‐activated protein kinase and lysosomal membrane‐associated protein 2, indicating a defect in autophagy. Also, induction of autophagy by tunicamycin resulted in apoptosis in diabetic PBMCs as observed by caspase‐3 cleavage and reduced expression of Bcl2. Inhibition of autophagy by bafilomycin rendered consistent expression of p62 indicating a defect in the final process of autophagy. Further, electron microscopic studies also confirmed massive vacuole overload and a sign of apoptotic cell death in PBMCs of diabetic patients, whereas metformin treatment reduced the number of autophagic vacuoles perhaps by lysosomal fusion. Thus, our results indicate that defective autophagy in T2D is associated with the fusion process of lysosomes which could be overcome by metformin.

show abstract

Metformin represses glucose starvation induced autophagic response in microvascular endothelial cells and promotes cell death

Cited by 35 publications

References 69 publications

Metformin: The Answer to Cancer in a Flower? Current Knowledge and Future Prospects of Metformin as an Anti-Cancer Agent in Breast Cancer

Metformin: The Answer to Cancer in a Flower? Current Knowledge and Future Prospects of Metformin as an Anti-Cancer Agent in Breast Cancer

Effects of oxidative and thermal stresses on stress granule formation in human induced pluripotent stem cells

The protective role of metformin in autophagic status in peripheral blood mononuclear cells of type 2 diabetic patients

Contact Info

Product

Resources

About