Metformin: From Diabetes to Cancer—Unveiling Molecular Mechanisms and Therapeutic Strategies
Abstract
:Simple Summary
Abstract
1. Introduction
Pharmacokinetics
2. Mechanisms of Action
2.1. Complex I Inhibition
2.2. Adenosine Monophosphate-Activated Protein Kinase (AMPK)-Dependent Mechanisms
Adenosine Monophosphate-Activated Protein Kinase (AMPK)-Dependent Lysosomal Pathway
2.3. Adenosine Monophosphate-Activated Protein Kinase (AMPK)-Independent Mechanisms
2.4. Complex IV Inhibition
2.5. Epigenetic Effects of Metformin
2.5.1. Effects of Metformin on the Acetylation Profile
2.5.2. DNA Methylation
2.6. Effects of Metformin on microRNAs
2.7. Effects of Metformin on the Microbiota
2.8. Effects of Metformin as an Anticancer Agent
3. Metformin in Cancer Risk and Treatment
3.1. Breast Cancer
3.1.1. Clinical Studies
3.1.2. Animal Studies
3.1.3. In Vitro Studies
3.2. Colorectal Cancer
3.2.1. Clinical Studies
3.2.2. Animal Studies
3.2.3. In Vitro Studies
4. Future Perspectives and Improvements in Cancer Therapy
5. Concluding Remarks
Author Contributions
Funding
Data Availability Statement
Conflicts of Interest
List of Abbreviations
5-FU | 5-fluorouracil |
ACC | Acetyl-CoA carboxylase |
ADP | Adenosine diphosphate |
AMP | Adenosine monophosphate |
AKT | Protein kinase B |
AMPK | AMP-activated protein kinase |
APC | Adenomatous polyposis coli |
ATP | Adenosine triphosphate |
AXIN | Axin 1 |
BMI | Body Mass Index |
CAMK-beta | Calcium/calmodulin protein kinase 2 |
CBP | CREB-binding protein |
CD133 | Cluster of differentiation 133 |
cAMP | Cyclic adenosine monophosphate |
cGPDH | Cytosolic glycerol-3-phosphate dehydrogenase |
CpG | Cytosine–phosphate–guanine |
CPT1 | Carnitine palmitoyltransferase 1 |
CRC | Colorectal cancer |
CREB | cAMP response element-binding protein |
CRTC2 | CREB-regulated transcription co-activator 2 |
CSC | Cancer stem cells |
CTL | Cytotoxic T lymphocyte |
CTLA4 | Cytotoxic T lymphocyte antigen 4 |
DICER1 | Dicer 1, Ribonuclease III |
DFS | Disease-free survival |
DFX | Deferasirox |
DHAP | Dihydroxyacetone phosphate |
DMH | Dimethylhydrazine |
DXR | Dexrazoxane |
EGF | Epidermal growth factor |
EMT | Epithelial–mesenchymal transition |
ER | Endoplasmic reticulum |
ERAD | ER-associated degradation |
ERK | Extracellular-Signal-Regulated Kinase |
FASN | Fatty acid synthase |
FXR | Farnesoid X receptor |
G3P | Glycerol-3-phosphate |
GDF15 | Growth/differentiation factor-15 |
GLOBOCAN | Global Cancer Observatory |
GLP1 | Glucagon-like peptide 1 |
GLUT1 | Glucose transport protein 1 |
GUDCA | Glycoursodeoxycholic acid |
H2S | Hydrogen sulfide |
HAT | Histone acetyltransferase |
HDAC | Histone deacetylase |
HNF-4α | hepatocyte nuclear factor-4α |
HER2- | Human epidermal growth factor receptor 2-negative |
HOMA-IR | Homeostatic model assessment for insulin resistance |
HR+ | Hormone receptor-positive |
IARC | International Agency for Research on Cancer |
IGF-1 | Insulin-like growth factor 1 |
ITC | Isothiocyanate |
KLF5 | Krüppel-like factor 5 |
Ki-67 | Antigen Kiel 67 |
LKB1 | Liver kinase B1 |
M-MDSCs | Monocytic myeloid-derived suppressor cells+B14 |
MAPK | Mitogen-activated protein kinases |
MATE | Multidrug and toxin extruders |
mGPDH | Mitochondrial glycerol-3-phosphate dehydrogenase |
MICB | MHC Class I Polypeptide-Related Sequence B |
miRNA | microRNA |
MMP-x | Matrix metalloproteinase-x |
mTOR | Mammalian target of rapamycin |
mTORC1 | Mammalian target of rapamycin complex 1 |
NADH | Nicotinamide adenine dinucleotide |
NAMPT | Nicotinamide phosphoribosyltransferase |
NDH1 | NADH–menaquinone oxidoreductase |
NDI1 | NADH–ubiquinone reductase (H(+)-translocating) |
NDUFS7 | NADH dehydrogenase [ubiquinone] iron-sulfur protein 7, mitochondrial |
NF-κB | Nuclear factor kappa-light-chain-enhancer of activated B cells |
OCMC | O-carboxymethyl-chitosan |
OCT | Organic cation transporter |
OS | Overall survival |
OXPHOS | Oxidative phosphorylation |
Pck1 | Phosphoenolpyruvate carboxykinase 1 |
PD-1 | Programmed cell death protein 1 |
PD-L1 | Programmed death-ligand 1 |
PEN2 | Presenilin enhancer 2 |
PET | Positron emission tomography |
PFK1 | Phosphofructokinase 1 |
PGC-1α | Peroxisome proliferator-activated receptor gamma coactivator 1-alpha |
PI3K | Phosphoinositide 3-kinase |
pKa | Acid dissociation constant |
PKA | Protein kinase A |
PKNOX2 | PBX/Knotted 1 Homeobox |
PMAT | Plasma membrane monoamine transporter |
PPI1 | Proton pump interactor isoform 1 |
PPP1R3C | Glycogen-targeting regulatory subunit of protein phosphatase 1 |
ROS | Reactive oxygen species |
S6K | Ribosomal protein S6 kinase |
SAH | S-adenosylhomocysteine |
SCFAs | Short chain fatty acid |
SESN1 | Sestrin 1 |
SHBG | Sex hormone-binding globulin |
SIRT1 | Sirtuin 1 |
T2DM | Type 2 diabetes mellitus |
TET3 | tet methylcytosine dioxygenase 3 |
TNBC | Triple-negative breast cancer |
TORC2 | Target of rapamycin complex 2 |
WDTC1 | WD And Tetratricopeptide Repeats 1 |
WNT | Wingless-type MMTV integration site family |
WZB117 | 2-fluoro-6-(m-hydroxybenzoyloxy) phenyl m-hydroxybenzoate |
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Function/Results | Disease | In Vitro/In Vivo | References |
---|---|---|---|
Complex I inhibition | Cancer, Diabetes | In vitro | [26,38,40,41,140,142,143,182,186] |
Apoptosis induction | Cancer | In vitro | [144,145] |
Induction of MMP-2, MMP-9, miR21, and miR-155 | Cancer | In vitro | [145] |
PI3K/Akt/NF-kB pathway inhibition | Cancer | In vitro | [146,191] |
Targeting KLF5 for degradation | Cancer | In vitro | |
Modulates miR-21-5p and SESN1 | Cancer | In vitro | [148] |
Cellular NAD+ depletion | Cancer | In vitro | [149] |
Reduction in cell proliferation by AMPK activation | Cancer | In vitro | [177,182] |
Reduction in cell proliferation by G0/G1 cell cycle arrest | Cancer | In vitro | [162,182] |
Activated ULK1 to stimulate an anti-tumor mitophagy program | Cancer | In vitro | [83] |
Enhanced cisplatin-induced apoptosis dependent on the generation of ROS | Cancer | In vitro | [185] |
Mitigation of DNA damage and mutagenesis by reducing ROS production | Cancer | In vitro | [178,188,189] |
Complex IV inhibition | Diabetes | In vitro | [60] |
Metformin-induced alterations in aspartate-malate shuttle and allosteric effectors of PFK1 and FBP1 | Diabetes | In vitro | [33] |
Activation of AMPK-dependent lysosomal pathway (AXIN/LKB1) at low doses: loss of GLP1 secretion upon PEN2 deletion | Diabetes | In vitro, in vivo | [53,54,185] |
Enhancement of mitochondrial function and anti-hyperglycemic effects by SIRT1 and SIRT3 modulation | Cancer, Diabetes | In vitro, in vivo | [67,76,187] |
Tumor burden, increased tumor latency, and slower tumor growth | Cancer | In vivo | [135] |
Local antitumor activity by reduction in M2-like macrophages, M-MDSCs, and Tregs | Cancer | In vivo | [138] |
Attenuation of doxorubicin-induced cardiotoxicity | Cancer | In vivo | [139] |
Suppression of colorectal aberrant crypt foci and intestinal polyps development, as well as liver metastasis by activating AMPK | Cancer | In vivo | [170,171,175] |
Metabolic changes decreasing oxygen consumption, activating AMPK pathway, and causing a reduction in cell growth | Cancer | In vivo | [173] |
Downregulation of tumor angiogenesis and cell proliferation | Cancer | In vivo | [172] |
Reduction in stem-like cell subpopulation | Cancer | In vivo | [174,190] |
Inhibition of the stimulatory effect of a high-energy diet on tumor growth: reduced insulin levels and AKT and FASN expression; changes in the gut microbiome | Cancer | In vivo | [178,180] |
Reduction in Ras-induced ROS production and associated DNA damage | Cancer | In vivo | [178] |
Enhanced the effectiveness of anti-PD-1 immunotherapy by mitigation of tumor hypoxia | Cancer | In vivo | [179] |
Reduced gluconeogenesis and hepatic lipid content by AMPK activation at suprapharmacological doses | Diabetes | In vivo | [47,48,51] |
Impairment in glucagon-stimulated glucose production by reduction in PKA activity | Diabetes | In vivo | [43,44,59] |
Suppression of cAMP-stimulated hepatic gluconeogenesis through HAT activity | Diabetes | In vivo | [63] |
Reduced gluconeogenesis and HbA1c associated with specific miRNAs modulation | Diabetes | In vivo | [86,88] |
Increase in SCFAs-producing bacteria | Diabetes | In vivo | [92,93,94,95] |
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Amengual-Cladera, E.; Morla-Barcelo, P.M.; Morán-Costoya, A.; Sastre-Serra, J.; Pons, D.G.; Valle, A.; Roca, P.; Nadal-Serrano, M. Metformin: From Diabetes to Cancer—Unveiling Molecular Mechanisms and Therapeutic Strategies. Biology 2024, 13, 302. https://doi.org/10.3390/biology13050302
Amengual-Cladera E, Morla-Barcelo PM, Morán-Costoya A, Sastre-Serra J, Pons DG, Valle A, Roca P, Nadal-Serrano M. Metformin: From Diabetes to Cancer—Unveiling Molecular Mechanisms and Therapeutic Strategies. Biology. 2024; 13(5):302. https://doi.org/10.3390/biology13050302
Chicago/Turabian StyleAmengual-Cladera, Emilia, Pere Miquel Morla-Barcelo, Andrea Morán-Costoya, Jorge Sastre-Serra, Daniel Gabriel Pons, Adamo Valle, Pilar Roca, and Mercedes Nadal-Serrano. 2024. "Metformin: From Diabetes to Cancer—Unveiling Molecular Mechanisms and Therapeutic Strategies" Biology 13, no. 5: 302. https://doi.org/10.3390/biology13050302