Restoration of mitochondria function as a target for cancer therapy

Bhat, Tariq A.; Kumar, Sandeep; Chaudhary, Ajay Kumar; Yadav, Neelu; Chandra, Dhyan

doi:10.1016/j.drudis.2015.03.001

Cited by 82 publications

(76 citation statements)

References 120 publications

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“…Because of this distinct feature in cancer, targeting PDK has been recognized as an effective anticancer therapeutic strategy. Numerous pre-clinical studies showed that a small molecule inhibitor of PDK, dichloroacetate (DCA), is effective in inhibiting proliferation of a wide range of cancers by reversing the glycolytic phenotype, depolarizing mitochondria, and inducing apoptosis (Bhat et al, 2015; Sutendra and Michelakis, 2013). Here, we provide evidence showing that PDK1 and PDK3 are overexpressed in prostate cancer cells, and that their overexpression is associated with advanced cancers.…”

Section: Discussionmentioning

confidence: 99%

KDM4A Coactivates E2F1 to Regulate the PDK-Dependent Metabolic Switch between Mitochondrial Oxidation and Glycolysis

Hung

Chen

et al. 2016

Cell Reports

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Summary The histone lysine demethylase KDM4A/JMJD2A has been implicated in prostate carcinogenesis through its role in transcriptional regulation. Here, we describe KDM4A as a E2F1 coactivator and demonstrate a functional role for the E2F1-KDM4A complex in the control of tumor metabolism. KDM4A associates with E2F1 on target gene promoters, enhances E2F1 chromatin binding and transcriptional activity, thereby modulating the transcriptional profile essential for cancer cell proliferation and survival. The pyruvate dehydrogenase kinases PDK1 and PDK3 are direct targets of KDM4A and E2F1, and modulate the switch between glycolytic metabolism and mitochondrial oxidation. Down regulation of KDM4A leads to elevated activity of pyruvate dehydrogenase and mitochondrial oxidation, resulting in excessive accumulation of reactive oxygen species. The altered metabolic phenotypes can be partially rescued by ectopic expression of PDK1 and PDK3, indicating a KDM4A-dependent tumor metabolic regulation via PDK. Our results suggest that KDM4A is a key regulator of tumor metabolism and a potential therapeutic target for prostate cancer.

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Section: Discussionmentioning

confidence: 99%

KDM4A Coactivates E2F1 to Regulate the PDK-Dependent Metabolic Switch between Mitochondrial Oxidation and Glycolysis

Hung

Chen

et al. 2016

Cell Reports

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“…82 Two key characteristics of mitochondria include mitochondrial DNA nucleoids anchored to the matrix side of the inner membrane, and the extremely negative membrane potential (−160 to −180 mV) caused by the proton gradient across its inner membrane. 83–85 The negative potential of the inner membrane attracts lipophilic cations, including metal complexes such as the Ru(II) complexes. The lipophilicity of Ru(II) complexes can be modulated by adjusting the ligands and the valence of complexes, which partly affects the uptake and targeting of Ru(II) complexes.…”

Section: The Cellular Uptake and Potential Targets Of Ru(ii) Complmentioning

confidence: 99%

The development of anticancer ruthenium(ii) complexes: from single molecule compounds to nanomaterials

et al. 2017

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Cancer is rapidly becoming the top killer in the world. Most of the FDA approved anticancer drugs are organic molecules, while metallodrugs are very scarce. The advent of first metal based therapeutic agent, cisplatin, launched a new era in the application of transition metal complexes for therapeutic design. Due to their unique and versatile biochemical properties, ruthenium-based compounds have emerged as promising anti-cancer agents that serve as alternatives to cisplatin and its derivertives. The ruthenium(III) complexes have successfully been used in clinical research and their mechanisms of anticancer action have been reported in large volumes over the past few decades. Ruthenium(II) complexes have also attracted significant attention as anticancer candidates; however, only few of them have been reported comprehensively. In this review, we discuss the development of ruthenium(II) complexes as anticancer candidates and biocatalysts, including arene ruthenium complexes, polypyridyl ruthenium complexes, and ruthenium nanomaterial complexes. This review focuses on the likely mechanisms of action of ruthenium(II)-based anticancer drugs and the relationship between their chemical structures and biological properties. This review also highlights the catalytic activity and the photoinduced activation of ruthenium(II) complexes, their targeted delivery, and their activity in nanomaterial systems.

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“…Most research efforts to target tumor metabolism have been directed toward inhibition of glycolysis (Doherty & Cleveland, 2013; Pelicano, Martin, Xu, & Huang, 2006). Only recently mitochondrial metabolism emerged as a chemotherapeutic target with most approaches attempting to inhibit mitochondrial metabolism in cancer cells (Bhat, Kumar, Chaudhary, Yadav, & Chandra, 2015; Weinberg & Chandel, 2015). The observation that the antidiabetic drug metformin decreased the prevalence of certain types of cancer triggered an interest in the role of mitochondrial inhibition as a mechanism to suppress abnormal cell proliferation (Giovannucci et al, 2010; Libby et al, 2009).…”

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

111

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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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Restoration of mitochondria function as a target for cancer therapy

Cited by 82 publications

References 120 publications

KDM4A Coactivates E2F1 to Regulate the PDK-Dependent Metabolic Switch between Mitochondrial Oxidation and Glycolysis

KDM4A Coactivates E2F1 to Regulate the PDK-Dependent Metabolic Switch between Mitochondrial Oxidation and Glycolysis

The development of anticancer ruthenium(ii) complexes: from single molecule compounds to nanomaterials

VDAC Regulation: A Mitochondrial Target to Stop Cell Proliferation

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