Metformin and cancer: Between the bioenergetic disturbances and the antifolate activity

Jara, José A.; López‐Muñoz, Rodrigo

doi:10.1016/j.phrs.2015.06.014

Cited by 40 publications

(34 citation statements)

References 74 publications

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“…451–453,456,457 Approved for antidiabetic treatment more than 20 years ago, metformin is now the most prescribed antidiabetic drug in the world. 454,458 Metformin is relatively safe, with minimal side effects.…”

Section: Mitochondria-targeted Therapeutics In the Pre-clinical Momentioning

confidence: 99%

Mitochondria-Targeted Triphenylphosphonium-Based Compounds: Syntheses, Mechanisms of Action, and Therapeutic and Diagnostic Applications

Zielonka¹,

Joseph²,

et al. 2017

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Mitochondria are recognized as one of the most important targets for new drug design in cancer, cardiovascular, and neurological diseases. Currently, the most effective way to deliver drugs specifically to mitochondria is by covalent linking a lipophilic cation such as an alkyltriphenylphosphonium moiety to a pharmacophore of interest. Other delocalized lipophilic cations, such as rhodamine, natural and synthetic mitochondria-targeting peptides, and nanoparticle vehicles, have also been used for mitochondrial delivery of small molecules. Depending on the approach used, and the potentials of cell and mitochondrial membranes, more than 1000-fold higher mitochondrial concentration can be achieved. Mitochondrial targeting has been developed to study mitochondrial physiology and dysfunction and the interaction between mitochondria and other subcellular organelles and for treatment of a variety of diseases such as neurodegeneration and cancer. In this review, we discuss efforts to target small-molecule compounds to mitochondria for probing mitochondria function, as diagnostic tools and potential therapeutics. We describe the physicochemical basis for mitochondrial accumulation of lipophilic cations, synthetic chemistry strategies to target compounds to mitochondria, mitochondrial probes and sensors, and examples of mitochondrial targeting of bioactive compounds. Finally, we review published attempts to apply mitochondria-targeted agents for the treatment of cancer and neurodegenerative diseases.

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Section: Mitochondria-targeted Therapeutics In the Pre-clinical Momentioning

confidence: 99%

Mitochondria-Targeted Triphenylphosphonium-Based Compounds: Syntheses, Mechanisms of Action, and Therapeutic and Diagnostic Applications

Zielonka¹,

Joseph²,

et al. 2017

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“…Although metformin decreases OXPHOS by inhibiting Complex I of the respiratory chain, it also inhibits the mammalian target of rapamycin (mTOR), interferes with folate metabolism, and activates AMP kinase. It is uncertain if the antiproliferative effect of metformin is actually due to OXPHOS inhibition (Jara & Lopez-Munoz, 2015). Other approaches to inhibit mitochondrial metabolism in various cancer cell models include etomoxir to inhibit carnitine O -palmitoyltransferase 1 and subsequently mitochondrial fatty acid oxidation (leukemia); tigecycline to inhibit mitochondrial protein translation (leukemia); glutaminase inhibitors (breast cancer, lymphoma); and the compound VLX600 to inhibit OXPHOS (colon cancer) (Samudio et al, 2010; Skrtic et al, 2011; Wang et al, 2010; Zhang et al, 2014).…”

Section: Tumor Metabolic Flexibility: Advantages Of Targeting Metabolmentioning

confidence: 99%

VDAC Regulation: A Mitochondrial Target to Stop Cell Proliferation

Fang

Maldonado

2018

Advances in Cancer Research

102

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Cancer metabolism is emerging as a chemotherapeutic target. Enhanced glycolysis and suppression of mitochondrial metabolism characterize the Warburg phenotype in cancer cells. The flux of respiratory substrates, ADP, and Pi into mitochondria and the release of mitochondrial ATP to the cytosol occur through voltage-dependent anion channels (VDACs) located in the mitochondrial outer membrane. Catabolism of respiratory substrates in the Krebs cycle generates NADH and FADH2 that enter the electron transport chain (ETC) to generate a proton motive force that maintains mitochondrial membrane potential (ΔΨ) and is utilized to generate ATP. The ETC is also the major cellular source of mitochondrial reactive oxygen species (ROS). αβ-Tubulin heterodimers decrease VDAC conductance in lipid bilayers. High constitutive levels of cytosolic free tubulin in intact cancer cells close VDAC decreasing mitochondrial ΔΨ and mitochondrial metabolism. The VDAC–tubulin interaction regulates VDAC opening and globally controls mitochondrial metabolism, ROS formation, and the intracellular flow of energy. Erastin, a VDAC-binding molecule lethal to some cancer cell types, and erastin-like compounds identified in a high-throughput screening antagonize the inhibitory effect of tubulin on VDAC. Reversal of tubulin inhibition of VDAC increases VDAC conductance and the flux of metabolites into and out of mitochondria. VDAC opening promotes a higher mitochondrial ΔΨ and a global increase in mitochondrial metabolism leading to high cytosolic ATP/ADP ratios that inhibit glycolysis. VDAC opening also increases ROS production causing oxidative stress that, in turn, leads to mitochondrial dysfunction, bioenergetic failure, and cell death. In summary, antagonism of the VDAC–tubulin interaction promotes cell death by a “double-hit model” characterized by reversion of the proproliferative Warburg phenotype (anti-Warburg) and promotion of oxidative stress.

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“…The lower prevalence of certain types of cancer in patients taking the antidiabetic drug metformin raised the interest on mitochondria as a potential target to suppress tumor growth (106, 107). Although the mechanism of action of metformin is not entirely clear, it has been shown to decrease OXPHOS by inhibiting complex I of ETC, to activate AMPK, to inhibit the mammalian target of rapamycin, and to interfere on folate metabolism (108). Other approaches to inhibit mitochondrial metabolism have included the use of glutaminase inhibitors (109), etomoxir to inhibit the carnitine O -palmitoyltransferase 1 and prevent subsequent mitochondrial fatty acid oxidation (110), the compound VLX600 to inhibit OXPHOS and reduce colon cancer tumor growth (111) and the antibiotic tigecycline to inhibit mitochondrial protein translation and decrease tumor growth in several experimental models of leukemia (112).…”

Section: Vdac–tubulin Antagonism Oxidative Stress and Reversal Of Wmentioning

confidence: 99%

VDAC–Tubulin, an Anti-Warburg Pro-Oxidant Switch

Maldonado

2017

Front. Oncol.

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Aerobic enhanced glycolysis characterizes the Warburg phenotype. In cancer cells, suppression of mitochondrial metabolism contributes to maintain a low ATP/ADP ratio that favors glycolysis. We propose that the voltage-dependent anion channel (VDAC) located in the mitochondrial outer membrane is a metabolic link between glycolysis and oxidative phosphorylation in the Warburg phenotype. Most metabolites including respiratory substrates, ADP, and Pi enter mitochondria only through VDAC. Oxidation of respiratory substrates in the Krebs cycle generates NADH that enters the electron transport chain (ETC) to generate a proton motive force utilized to generate ATP and to maintain mitochondrial membrane potential (ΔΨ). The ETC is also the major source of mitochondrial reactive oxygen species (ROS) formation. Dimeric α-β tubulin decreases conductance of VDAC inserted in lipid bilayers, and high free tubulin in cancer cells by closing VDAC, limits the ingress of respiratory substrates and ATP decreasing mitochondrial ΔΨ. VDAC opening regulated by free tubulin operates as a “master key” that “seal–unseal” mitochondria to modulate mitochondrial metabolism, ROS formation, and the intracellular flow of energy. Erastin, a small molecule that binds to VDAC and kills cancer cells, and erastin-like compounds antagonize the inhibitory effect of tubulin on VDAC. Blockage of the VDAC–tubulin switch increases mitochondrial metabolism leading to decreased glycolysis and oxidative stress that promotes mitochondrial dysfunction, bioenergetic failure, and cell death. In summary, VDAC opening-dependent cell death follows a “metabolic double-hit model” characterized by oxidative stress and reversion of the pro-proliferative Warburg phenotype.

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Metformin and cancer: Between the bioenergetic disturbances and the antifolate activity

Cited by 40 publications

References 74 publications

Mitochondria-Targeted Triphenylphosphonium-Based Compounds: Syntheses, Mechanisms of Action, and Therapeutic and Diagnostic Applications

Mitochondria-Targeted Triphenylphosphonium-Based Compounds: Syntheses, Mechanisms of Action, and Therapeutic and Diagnostic Applications

VDAC Regulation: A Mitochondrial Target to Stop Cell Proliferation

VDAC–Tubulin, an Anti-Warburg Pro-Oxidant Switch

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