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

Chemical Reviews, Journal Year: 2017, Volume and Issue: 117(15), P. 10043 - 10120

Published: June 27, 2017

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

Language: Английский

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Glutamine blockade induces divergent metabolic programs to overcome tumor immune evasion

Science, Journal Year: 2019, Volume and Issue: 366(6468), P. 1013 - 1021

Published: Nov. 8, 2019

The metabolic characteristics of tumors present considerable hurdles to immune cell function and cancer immunotherapy. Using a glutamine antagonist, we metabolically dismantled the immunosuppressive microenvironment tumors. We demonstrate that blockade in tumor-bearing mice suppresses oxidative glycolytic metabolism cells, leading decreased hypoxia, acidosis, nutrient depletion. By contrast, effector T cells responded antagonism by markedly up-regulating adopting long-lived, highly activated phenotype. These divergent changes cellular programming form basis for potent antitumor responses. Glutamine therefore exposes previously undefined difference plasticity between can be exploited as "metabolic checkpoint" tumor

Language: Английский

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The hallmarks of cancer metabolism: Still emerging

Cell Metabolism, Journal Year: 2022, Volume and Issue: 34(3), P. 355 - 377

Published: Feb. 4, 2022

Language: Английский

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Lactate in the Regulation of Tumor Microenvironment and Therapeutic Approaches

Frontiers in Oncology, Journal Year: 2019, Volume and Issue: 9

Published: Nov. 1, 2019

Tumor cells must generate sufficient ATP and biosynthetic precursors in order to maintain cell proliferation requirements. Otto Warburg showed that tumor uptake high amounts of glucose producing large volumes lactate even the presence oxygen, this process is known as "Warburg effect or aerobic glycolysis". As a consequence such there an acidification extracellular pH microenvironment, ranging between 6.0-6.5. This acidosis favors processes metastasis, angiogenesis more importantly, immunosuppression, which has been associated worse clinical prognosis. Thus, should be thought important oncometabolite metabolic reprogramming cancer. In review, we summarized role regulating microenvironment cancer discuss its relevance up-regulation enzymes dehydrogenase (LDH) monocarboxilate transporters (MCTs) tumors. The goal review expose not only secondary product cellular waste cells, but also key molecule involved carcinogenesis well immune evasion. Finally, possible targeting production treatment discussed.

Language: Английский

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The Warburg effect: essential part of metabolic reprogramming and central contributor to cancer progression

International Journal of Radiation Biology, Journal Year: 2019, Volume and Issue: 95(7), P. 912 - 919

Published: March 1, 2019

In the early 1920s, Warburg published experimental data on enhanced conversion of glucose to pyruvate (followed by lactate formation) even in presence abundant oxygen (aerobic glycolysis, effect). He attributed this metabolic trait a respiratory injury and considered universal alteration carcinogenesis. This interpretation was questioned since 1950s. Realistic causative mechanisms consequences effect were described only during past 15 years are summarized article. There is clear evidence that mitochondria not defective most cancers. Aerobic key feature phenotype, caused active reprogramming required support sustained cancer cell proliferation malignant progression. switch directed altered growth factor signaling, hypoxic or normoxic activation HIF-1α- transcription, oncogene loss-of-function suppressor genes, implemented hostile tumor microenvironment. The 'selfish' includes (a) overexpression transporters glycolytic enzymes, an accelerated flux with subsequent accumulation diversion intermediates for biomass synthesis, (b) high-speed ATP production meets energy demand, (c) which drives progression largely contributes acidosis, turn synergistically favors resistance certain antitumor therapies, compromises immunity. Altogether, central contributor machinery.

Language: Английский

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The machineries, regulation and cellular functions of mitochondrial calcium

Nature Reviews Molecular Cell Biology, Journal Year: 2018, Volume and Issue: 19(11), P. 713 - 730

Published: Aug. 24, 2018

Language: Английский

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Aerobic glycolysis promotes T helper 1 cell differentiation through an epigenetic mechanism

Science, Journal Year: 2016, Volume and Issue: 354(6311), P. 481 - 484

Published: Sept. 30, 2016

Aerobic glycolysis (the Warburg effect) is a metabolic hallmark of activated T cells and has been implicated in augmenting effector cell responses, including expression the proinflammatory cytokine interferon-γ (IFN-γ), via 3' untranslated region (3'UTR)-mediated mechanisms. Here, we show that lactate dehydrogenase A (LDHA) induced to support aerobic but promotes IFN-γ independently its 3'UTR. Instead, LDHA maintains high concentrations acetyl-coenzyme enhance histone acetylation transcription Ifng Ablation protects mice from immunopathology triggered by excessive or deficiency regulatory cells. These findings reveal an epigenetic mechanism which differentiation suggest may be targeted therapeutically autoinflammatory diseases.

Language: Английский

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Unraveling the Complex Interplay Between T Cell Metabolism and Function

Annual Review of Immunology, Journal Year: 2018, Volume and Issue: 36(1), P. 461 - 488

Published: April 20, 2018

Metabolism drives function, on both an organismal and a cellular level. In T cell biology, metabolic remodeling is intrinsically linked to development, activation, differentiation, survival. After naive cells are activated, increased demands for currency in the form of ATP, as well biomass growth, proliferation, production effector molecules, met by rewiring metabolism. Consequently, pharmacological strategies being developed perturb or enhance selective processes that skewed immune-related pathologies. Here we review most recent advances describing changes occur during lifecycle. We discuss how metabolism can have profound effects health disease where it might be promising target treat variety

Language: Английский

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Lactate metabolism in human health and disease

Signal Transduction and Targeted Therapy, Journal Year: 2022, Volume and Issue: 7(1)

Published: Sept. 1, 2022

Abstract The current understanding of lactate extends from its origins as a byproduct glycolysis to role in tumor metabolism, identified by studies on the Warburg effect. shuttle hypothesis suggests that plays an important bridging signaling molecule coordinates among different cells, organs and tissues. Lactylation is posttranslational modification initially reported Professor Yingming Zhao’s research group 2019. Subsequent confirmed lactylation vital component function involved proliferation, neural excitation, inflammation other biological processes. An indispensable substance for various physiological cellular functions, regulatory aspects energy metabolism signal transduction. Therefore, comprehensive review summary presented clarify disease provide reference direction future research. This offers systematic overview homeostasis roles pathological processes, well effects diseases, particularly cancer.

Language: Английский

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METTL3-mediated m⁶A modification of HDGF mRNA promotes gastric cancer progression and has prognostic significance

Gut, Journal Year: 2019, Volume and Issue: 69(7), P. 1193 - 1205

Published: Oct. 3, 2019

Objective N 6 -methyladenosine (m A) RNA methylation and its associated methyltransferase METTL3 are involved in tumour initiation progression via the regulation of function. This study explored biological function clinical significance gastric cancer (GC). Design The prognostic value expression was evaluated using tissue microarray immunohistochemical staining analyses a human GC cohort. role mechanism growth liver metastasis were determined vitro vivo. Results level m A significantly increased GC, main regulator abundant modification. elevated tissues with poor prognosis. Multivariate Cox regression analysis revealed that an independent factor effective predictor patients GC. Moreover, overexpression promoted proliferation Mechanistically, P300-mediated H3K27 acetylation activation promoter induced transcription, which stimulated modification HDGF mRNA, reader IGF2BP3 then directly recognised bound to site on mRNA enhanced stability. Secreted angiogenesis, while nuclear activated GLUT4 ENO2 expression, followed by increase glycolysis cells, correlated subsequent metastasis. Conclusions Elevated promotes angiogenesis indicating is potential biomarker therapeutic target for

Language: Английский

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