Dichloroacetic Acid (DCA)-Induced  Cytotoxicity in Human Breast Cancer Cells Accompanies Changes in Mitochondrial Membrane Permeability and Production of Reactive Oxygen Species

Al-Karakooly, Zeiyad; Kilaparty, Surya P.; Al-Anbaky, Qudes; Khan, Mohammad Saeed; Ali, Nawab

doi:10.4236/jct.2014.513125

Cited by 7 publications

(10 citation statements)

References 31 publications

(49 reference statements)

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“…As DCA-mediated increase in ROS production is known to induce oxidative cellular damage and apoptosis in breast cancer and myeloma cells 36 , 39 , we investigated whether treatment of PGL cells with DCA was associated with promotion of apoptosis. As indicated by flow cytometry evaluation of Annexin-V staining, DCA treatment resulted in a significant induction of apoptosis in both cell lines (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…DCA has shown a promising role as cancer treatment, since it appears more tolerated than standard cytotoxic chemotherapy 39 . In this regard, an open-label, phase 1 trial using oral DCA in patients with recurrent glioblastoma showed that chronic oral assumption of DCA is a feasible and well-tolerated drug treatment in patients with malignant gliomas 44 .…”

Section: Discussionmentioning

confidence: 99%

“…The interaction among DCA, GW6471 and metformin was quantified by determining the combination index (CI). The CI was calculated by CompuSyn software using the Chou-Talalay equation 39 . Based on this equation CI < 1 indicates synergistic effects, CI = 1 indicates additive effects and CI > 1 indicates antagonistic effects.…”

Section: Methodsmentioning

confidence: 99%

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Effects of dichloroacetate as single agent or in combination with GW6471 and metformin in paraganglioma cells

Florio

Lellis

Veschi

et al. 2018

Sci Rep

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Paragangliomas (PGLs) are infiltrating autonomic nervous system tumors that cause important morbidity. At present, surgery is the only effective therapeutic option for this rare tumor. Thus, new agents for PGL treatment should be identified. Using unique PGL cell models established in our laboratory, we evaluated the effect of dichloroacetate (DCA) as single agent or in a novel combination with other metabolic drugs, including GW6471 and metformin. DCA and metformin had not been tested before in PGL. DCA reduced PGL cell viability and growth through mechanisms involving reactivation of PDH complex leading to promotion of oxidative metabolism, with lowering of lactate and enhanced ROS production. This resulted in cell cycle inhibition and induction of apoptosis in PGL cells, as shown by flow cytometry and immunoblot analyses. Moreover, DCA drastically impaired clonogenic activity and migration of PGL cells. Also metformin reduced PGL cell viability as single agent and the combinations of DCA, GW6471 and metformin had strong effects on cell viability. Furthermore, combined treatments had drastic and synergistic effects on clonogenic ability. In conclusion, DCA, GW6471 and metformin as single agents and in combination appear to have promising antitumor effects in unique cell models of PGL.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Effects of dichloroacetate as single agent or in combination with GW6471 and metformin in paraganglioma cells

Florio

Lellis

Veschi

et al. 2018

Sci Rep

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“…Dichloroacetic acid (DCA) is an analogue of acetic acid, and has a broad range of therapeutic applications in various diseases, including lactic acidosis, topical chemoablation, and cancers, due to its ability to inhibit the enzyme pyruvate dehydrogenase kinase . DCA can not only decrease mitochondrial membrane potential, but also enhance ROS levels in cancer cells, leading to cytotoxicity .…”

Section: Introductionmentioning

confidence: 99%

Synergistic Amplification of Oxidative Stress–Mediated Antitumor Activity via Liposomal Dichloroacetic Acid and MOF‐Fe²⁺

Sun

Gao

et al. 2019

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Cancer cells are susceptible to oxidative stress; therefore, selective elevation of intracellular reactive oxygen species (ROS) is considered as an effective antitumor treatment. Here, a liposomal formulation of dichloroacetic acid (DCA) and metal–organic framework (MOF)‐Fe2+ (MD@Lip) has been developed, which can efficiently stimulate ROS‐mediated cancer cell apoptosis in vitro and in vivo. MD@Lip can not only improve aqueous solubility of octahedral MOF‐Fe2+, but also generate an acidic microenvironment to activate a MOF‐Fe2+‐based Fenton reaction. Importantly, MD@Lip promotes DCA‐mediated mitochondrial aerobic oxidation to increase intracellular hydrogen peroxide (H2O2), which can be consequently converted to highly cytotoxic hydroxyl radicals (•OH) via MOF‐Fe2+, leading to amplification of cancer cell apoptosis. Particularly, MD@Lip can selectively accumulate in tumors, and efficiently inhibit tumor growth with minimal systemic adverse effects. Therefore, liposome‐based combination therapy of DCA and MOF‐Fe2+ provides a promising oxidative stress–associated antitumor strategy for the management of malignant tumors.

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“…Pyruvate dehydrogenase kinase (PDK) 1 is a key factor in the connection between glycolysis and mitochondrial OXPHOS and is highly expressed in most tumor cells. 5 , 6 Tumor cells with high expression of PDK1 have anti-apoptotic activity. 7 , 8 PDK1 phosphorylates pyruvate dehydrogenase (PDH) to inhibit its activity, thus reducing available pyruvate for mitochondrial metabolism.…”

Section: Introductionmentioning

confidence: 99%

<p>Dichloroacetic acid upregulates apoptosis of ovarian cancer cells by regulating mitochondrial function</p>

Zhou

Liu

Chai

et al. 2019

OTT

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BackgroundMetabolic reprogramming is a characteristic of tumor cells and is considered a potential therapeutic target. Even under aerobic conditions, tumor cells use glycolysis to produce energy, a phenomenon called the “Warburg effect”. Pyruvate dehydrogenase kinase 1 (PDK1) is a key factor linking glycolysis and the tricarboxylic acid cycle. Dichloroacetic acid (DCA) reverses the Warburg effect by inhibition of PDK1 to switch cytoplasmic glucose metabolism to mitochondrial oxidative phosphorylation (OXPHOS).MethodsCell viability was examined using a standard MTT assay. Glucose consumption and l-lactate production were measured using commercial colorimetric kits, and intracellular lactate dehydrogenase (LDH) activity was evaluated using cell lysates and an LDH Quantification Kit. Real-time PCR was used to detect the expression of related genes. The production of total ROS was evaluated by staining with dichlorofluorescin diacetate.ResultsComparison of various aspects of glucose metabolism, such as expression of key enzymes in glycolysis, lactate production, glucose consumption, mitochondrial oxygen consumption rate, and citric acid production, revealed that A2780/DDP cells were primarily dependent on glycolysis whereas A2780 cells were primarily dependent on mitochondrial OXPHOS. Mitochondrial uncoupling protein 2 (UCP2) protects against mitochondrial ROS while allowing energy metabolism to switch to glycolysis. Treatment of A2780 cells with various concentrations of DCA resulted in decreased expression of UCP2, a metabolic switch from glycolysis to mitochondrial OXPHOS, and an increase in oxidative stress induced by ROS. These effects were not observed in A2780/DDP cells with higher UCP2 expression suggesting that UCP2 might induce changes in mitochondrial functions that result in different sensitivities to DCA.ConclusionOur results show that a drug targeting tumor metabolic changes affects almost the entire process of glucose metabolism. Thus, it is necessary to comprehensively determine tumor metabolic functions to facilitate individualized antitumor therapy.

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Dichloroacetic Acid (DCA)-Induced Cytotoxicity in Human Breast Cancer Cells Accompanies Changes in Mitochondrial Membrane Permeability and Production of Reactive Oxygen Species

Cited by 7 publications

References 31 publications

Effects of dichloroacetate as single agent or in combination with GW6471 and metformin in paraganglioma cells

Effects of dichloroacetate as single agent or in combination with GW6471 and metformin in paraganglioma cells

Synergistic Amplification of Oxidative Stress–Mediated Antitumor Activity via Liposomal Dichloroacetic Acid and MOF‐Fe²⁺

<p>Dichloroacetic acid upregulates apoptosis of ovarian cancer cells by regulating mitochondrial function</p>

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Dichloroacetic Acid (DCA)-Induced Cytotoxicity in Human Breast Cancer Cells Accompanies Changes in Mitochondrial Membrane Permeability and Production of Reactive Oxygen Species

Cited by 7 publications

References 31 publications

Effects of dichloroacetate as single agent or in combination with GW6471 and metformin in paraganglioma cells

Effects of dichloroacetate as single agent or in combination with GW6471 and metformin in paraganglioma cells

Synergistic Amplification of Oxidative Stress–Mediated Antitumor Activity via Liposomal Dichloroacetic Acid and MOF‐Fe2+

<p>Dichloroacetic acid upregulates apoptosis of ovarian cancer cells by regulating mitochondrial function</p>

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Synergistic Amplification of Oxidative Stress–Mediated Antitumor Activity via Liposomal Dichloroacetic Acid and MOF‐Fe²⁺