Discovery of a new mitochondria permeability transition pore (mPTP) inhibitor based on gallic acid

Teixeira, José; Oliveira, Catarina; Cagide, Fernando; Amorim, Ricardo; Garrido, Jorge; Oliveira, Paulo J.

doi:10.1080/14756366.2018.1442831

Cited by 19 publications

(14 citation statements)

References 52 publications

(57 reference statements)

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“…A number of alternative approaches for mPTP inhibition have been reported, probably acting via inhibiting pathways upstream to mPTP opening, including modulation of mitochondrial redox state [10,82,83], ETC function [84] and Ca 2+ influx (REF). The most significant achievement to date is the approval of Edaravone (Radicut™) [10] (Box 2), a potent anti-oxidant and inhibitor of mPTP opening and having demonstrated protection in multiple models [85,86].…”

Section: Cypd-independent Inhibitors Of Mptp Openingmentioning

confidence: 99%

“…The most significant achievement to date is the approval of Edaravone (Radicut™) [10] (Box 2), a potent anti-oxidant and inhibitor of mPTP opening and having demonstrated protection in multiple models [85,86]. The mitochondrial targeted antioxidant (AntiOxBEN3), targeted to mitochondria by conjugation with triphenylphosphonium (TPP + ), delayed Ca 2+ -induced mPTP opening and protected against iron-and hydrogen peroxide-induced cytotoxicity [82].…”

Section: Cypd-independent Inhibitors Of Mptp Openingmentioning

confidence: 99%

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Mitochondrial Permeability Transition: A Molecular Lesion with Multiple Drug Targets

Briston

Selwood

Szabadkai

et al. 2019

Trends in Pharmacological Sciences

145

123

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Mitochondrial permeability transition, as the consequence of opening of a mitochondrial permeability transition pore (mPTP), is a cellular catastrophe. Initiating bioenergetic collapse and cell death, it has been implicated in the pathophysiology of major human diseases, including neuromuscular diseases of childhood, ischaemia-reperfusion injury and age related neurodegenerative disease. mPTP represents a major therapeutic target, as opening can be prevented by a number of compounds. However, clinical studies have so far been disappointing. We therefore address the prospects and challenges faced in translating in vitro findings to clinical benefit. We review the role of mPTP opening in disease, discuss recent findings defining the putative structure of mPTP and explore strategies to identify

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Section: Cypd-independent Inhibitors Of Mptp Openingmentioning

confidence: 99%

Section: Cypd-independent Inhibitors Of Mptp Openingmentioning

confidence: 99%

Mitochondrial Permeability Transition: A Molecular Lesion with Multiple Drug Targets

Briston

Selwood

Szabadkai

et al. 2019

Trends in Pharmacological Sciences

145

123

View full text Add to dashboard Cite

show abstract

“…Experimentally, GA has been documented to produce anti-hyperlipidemic, cardioprotective, anti-diabetic activity [32,33]. Furthermore, GA has potential neuroprotective action due to mono and poly-targeted actions [34,35]. In addition, an acute and sub-acute toxicity study of GA (5000 mg/kg; per oral) documented that, GA did not produce any serious adverse effects and organ toxicity [36].…”

Section: Introductionmentioning

confidence: 99%

Ameliorative effect of gallic acid in paclitaxel-induced neuropathic pain in mice

Kaur¹,

Muthuraman

2019

Toxicology Reports

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“…This altered mitochondrial metabolism of cancer cells compared with that of their normal counterparts is advantageous for the selective targeting of cancer mitochondria in therapeutics, which focuses on the cancer mitochondria specific features [18]. Directing the therapeutic agent to the mitochondria is an efficient way of eliminating cancer cells because the designed drug molecules could act at the central point of the cell, and therefore, engineering mitochondrial-targeted therapeutic agents have gained much interest in cancer therapy.Anticancer drugs that selectively disrupt cancerous mitochondria could be achieved by designing molecules that act on the malignant mitochondria by, for instance, inhibiting glycolysis, depolarizing the membrane potential, and inhibiting the mitochondrial permeability transition pore [19,20]. However, penetrating the double-layered membrane of mitochondria requires overcoming certain barriers.…”

mentioning

confidence: 99%

“…Anticancer drugs that selectively disrupt cancerous mitochondria could be achieved by designing molecules that act on the malignant mitochondria by, for instance, inhibiting glycolysis, depolarizing the membrane potential, and inhibiting the mitochondrial permeability transition pore [19,20]. However, penetrating the double-layered membrane of mitochondria requires overcoming certain barriers.…”

mentioning

confidence: 99%

Recent Progress in Mitochondria-Targeted Drug and Drug-Free Agents for Cancer Therapy

Jeena

Kim

Jin

et al. 2019

Cancers

107

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The mitochondrion is a dynamic eukaryotic organelle that controls lethal and vital functions of the cell. Being a critical center of metabolic activities and involved in many diseases, mitochondria have been attracting attention as a potential target for therapeutics, especially for cancer treatment. Structural and functional differences between healthy and cancerous mitochondria, such as membrane potential, respiratory rate, energy production pathway, and gene mutations, could be employed for the design of selective targeting systems for cancer mitochondria. A number of mitochondria-targeting compounds, including mitochondria-directed conventional drugs, mitochondrial proteins/metabolism-inhibiting agents, and mitochondria-targeted photosensitizers, have been discussed. Recently, certain drug-free approaches have been introduced as an alternative to induce selective cancer mitochondria dysfunction, such as intramitochondrial aggregation, self-assembly, and biomineralization. In this review, we discuss the recent progress in mitochondria-targeted cancer therapy from the conventional approach of drug/cytotoxic agent conjugates to advanced drug-free approaches.In healthy cells, mitochondria execute a controlled regulation of multiple functions to maintain the cellular growth-death cycle. However, in the case of tumor cells, to meet the higher metabolic demand of rapidly proliferating cells, dysregulation of mitochondrial metabolism occurs [14,15]. The difference between cancer cell mitochondria and normal cells includes several functional alterations, such as mutation of mtDNA that lead to OXPHOS (oxidative phosphorylation) inhibition and thus deficient respiration and ATP generation, mutation of mtDNA-encoded mitochondrial enzymes, such as SDH (succinate dehydrogenase), IDH1 (isocitrate dehydrogenase 1), IDH2 (isocitrate dehydrogenase 2) [16], and structural differences, such as higher membrane potential of cancer cell mitochondria and higher basicity inside the mitochondrial lumen. The evasion of cell death or inhibition of mitochondria-mediated apoptosis is a hallmark for cancer. Mitochondria generate ROS, which is necessary for signaling under normal conditions. However, when apoptosis is inhibited in the case of cancer, ROS contributes to the neoplastic transformation. Furthermore, for supporting tumor cell survival under harsh tumorigenic conditions, such as nutrient depletion and hypoxia, mitochondria provide flexibility in several pathways either by up-or downregulation [17]. This altered mitochondrial metabolism of cancer cells compared with that of their normal counterparts is advantageous for the selective targeting of cancer mitochondria in therapeutics, which focuses on the cancer mitochondria specific features [18]. Directing the therapeutic agent to the mitochondria is an efficient way of eliminating cancer cells because the designed drug molecules could act at the central point of the cell, and therefore, engineering mitochondrial-targeted therapeutic agents have gained much interest in cancer thera...

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Discovery of a new mitochondria permeability transition pore (mPTP) inhibitor based on gallic acid

Cited by 19 publications

References 52 publications

Mitochondrial Permeability Transition: A Molecular Lesion with Multiple Drug Targets

Mitochondrial Permeability Transition: A Molecular Lesion with Multiple Drug Targets

Ameliorative effect of gallic acid in paclitaxel-induced neuropathic pain in mice

Recent Progress in Mitochondria-Targeted Drug and Drug-Free Agents for Cancer Therapy

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