Mitochondria as an important target of metformin: The mechanism of action, toxic and side effects, and new therapeutic applications

Jin, Feng; Wang, Xiaohui; Ye, Xiaochun; Arés, Irma; López-Torres, Bernardo; Martínez, Marta; Martínez-Larrañaga, María-Rosa; Wang, Xu; Anadón, Arturo; Martínez, María-Aránzazu

doi:10.1016/j.phrs.2022.106114

Cited by 78 publications

(46 citation statements)

References 229 publications

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“…Therefore, researchers are seeking new strategies to achieve a competitive advantage in targeting mitochondria for cancer therapy. Redevelopment and reuse of old drugs (repurposing/repositioning) represent such an opportunity to replenish the inventory of mitochondrial-targeted antitumor drugs [ 224 ]. Besides, the use of targeted nanomedicines offers innovative therapeutic strategies to overcome multiple barriers and selectively transport drug molecules to the mitochondria [ 319 , 320 ].…”

Section: Strategies For Overcoming Mitochondria-targeting Bottlenecks...mentioning

confidence: 99%

Mitochondrial adaptation in cancer drug resistance: prevalence, mechanisms, and management

et al. 2022

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Drug resistance represents a major obstacle in cancer management, and the mechanisms underlying stress adaptation of cancer cells in response to therapy-induced hostile environment are largely unknown. As the central organelle for cellular energy supply, mitochondria can rapidly undergo dynamic changes and integrate cellular signaling pathways to provide bioenergetic and biosynthetic flexibility for cancer cells, which contributes to multiple aspects of tumor characteristics, including drug resistance. Therefore, targeting mitochondria for cancer therapy and overcoming drug resistance has attracted increasing attention for various types of cancer. Multiple mitochondrial adaptation processes, including mitochondrial dynamics, mitochondrial metabolism, and mitochondrial apoptotic regulatory machinery, have been demonstrated to be potential targets. However, recent increasing insights into mitochondria have revealed the complexity of mitochondrial structure and functions, the elusive functions of mitochondria in tumor biology, and the targeting inaccessibility of mitochondria, which have posed challenges for the clinical application of mitochondrial-based cancer therapeutic strategies. Therefore, discovery of both novel mitochondria-targeting agents and innovative mitochondria-targeting approaches is urgently required. Here, we review the most recent literature to summarize the molecular mechanisms underlying mitochondrial stress adaptation and their intricate connection with cancer drug resistance. In addition, an overview of the emerging strategies to target mitochondria for effectively overcoming chemoresistance is highlighted, with an emphasis on drug repositioning and mitochondrial drug delivery approaches, which may accelerate the application of mitochondria-targeting compounds for cancer therapy.

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Section: Strategies For Overcoming Mitochondria-targeting Bottlenecks...mentioning

confidence: 99%

Mitochondrial adaptation in cancer drug resistance: prevalence, mechanisms, and management

et al. 2022

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“…Recent studies reported that metformin reduced ROS production by mitochondrial complex I (NADH: ubiquinone oxidoreductase) and improved oxidative stress-mediated dysfunction or cell apoptosis 130 . PGC-1α is a co-transcriptional regulator that promotes mitochondrial biogenesis.…”

Section: Molecular Mechanisms and Signal Transduction Pathwaysmentioning

confidence: 99%

Metformin in aging and aging-related diseases: clinical applications and relevant mechanisms

et al. 2022

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Aging is a natural process, which plays a critical role in the pathogenesis of a variety of diseases, i.e., aging-related diseases, such as diabetes, osteoarthritis, Alzheimer disease, cardiovascular diseases, cancers, obesity and other metabolic abnormalities. Metformin, the most widely used antidiabetic drug, has been reported to delay aging and display protective effect on attenuating progression of various aging-related diseases by impacting key hallmark events of aging, including dysregulated nutrient sensing, loss of proteostasis, mitochondrial dysfunction, altered intercellular communication, telomere attrition, genomic instability, epigenetic alterations, stem cell exhaustion and cellular senescence. In this review, we provide updated information and knowledge on applications of metformin in prevention and treatment of aging and aging-related diseases. We focus our discussions on the roles and underlying mechanisms of metformin in modulating aging and treating aging-related diseases.

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“…This expected to be a factor affecting on the salivary secretion and function, which may be related to its structural composition as metformin hydrochloride, a hydrophilic drug and/or its use may associate with lactic acidosis. 7 Ahmadinia et al had conducted a recent systematic review and meta-analysis to study Association between T2DM and tooth loss, found that a positive association between T2DM and tooth loss in cross-sectional studies and no significant association between T2DM and tooth loss was found in cohort studies with increase the risk of oral disease in T2DM directly (e.g., gingival inflammatory response) and indirectly (e.g., decreased saliva production due to medication e.g., metformin). 9 These results in agree with our findings that antidiabetic drugs may effect on salivary gland secretion and later lead to xerostomia and increase risk of developing dental erosion and attrition, due to loss of salivary protection of the teeth against acids, extrinsic or intrinsic factors which causing these conditions.…”

Section: Srisilapanan Et Al Who Researchedmentioning

confidence: 99%

“…Its distribution mainly depends on tissue-specific transporters. 7 The mechanism works Metformin by increasing peripheral glucose uptake, reducing intestinal glucose absorption, increasing insulin sensitivity, and decreasing fasting plasma insulin levels, thereby reducing blood glucose concentrations without causing hypoglycemia. In addition, Metformin can inhibit gluconeogenesis by activating AMPactivated protein kinase.…”

Section: Introductionmentioning

confidence: 99%

“…The risk of lactic acidosis increases with the degree of renal impairment and the patient's age. 7 Insulin has the advantage of being effective in management of T2DM where other antidiabetic drugs are not and should be considered as part of any combination regimen when hyperglycemia is severe, especially if catabolic features (weight loss, hypertriglyceridemia, ketosis) are present and It is common practice to initiate insulin therapy for patients who present with blood glucose levels ≥ 300 mg/dl or A1C >10% or if the patient has symptoms of hyperglycemia (i.e., polyuria or polydipsia) or evidence of catabolism (weight loss). 6 Diabetes increases the risk of oral disease directly (e.g., gingival inflammatory response) and indirectly (e.g., decreased saliva production due to medication).…”

Section: Introductionmentioning

confidence: 99%

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The effect of Insulin and Metformin on Prevalence and Severity of Tooth Wear in type2 Diabetic Patients.

Younes

Hamam

2022

Egyptian Dental Journal

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Purpose: Investigating the effect of insulin and metformin on the prevalence and severity of tooth wear in patients with type 2 diabetes. Patients and methods:This cross -sectional study was conducted on194 Egyptian adult diabetic type 2 patients, age group (50-70) using quota sampling method, assessing the prevalence and severity of tooth wear in adults of the included region. Three-stage stratification was done by sex, age and type of diabetes, then classified in to two groups: Group A: 105 patients treated with insulin regimens without metformin and stop metformin at least 5 years ago. Group B: 89 patients treated with metformin only. Measuring the tooth wear by Smith and Knight Tooth Wear Index (TWI).Results: Teeth Wear index (TWI) was significantly positively correlated to age and duration of diabetes in all groups. Treatment with metformin was a significant positive predictor of TWI. TWI was 1.857 higher on average for those who use metformin as compared to those who use insulin. Conclusion:There was a significant difference between different TWI as regard age and duration of diabetes. Any factor changes the oral salivary PH and viscosity will effect on the tooth wear severity.

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Mitochondria as an important target of metformin: The mechanism of action, toxic and side effects, and new therapeutic applications

Cited by 78 publications

References 229 publications

Mitochondrial adaptation in cancer drug resistance: prevalence, mechanisms, and management

Mitochondrial adaptation in cancer drug resistance: prevalence, mechanisms, and management

Metformin in aging and aging-related diseases: clinical applications and relevant mechanisms

The effect of Insulin and Metformin on Prevalence and Severity of Tooth Wear in type2 Diabetic Patients.

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