Abstract
A hypoxic microenvironment is a hallmark in different types of tumors; this phenomenon participates in a metabolic alteration that confers resistance to treatments. Because of this, it was proposed that a combination of 2-methoxyestradiol (2-ME) and sodium dichloroacetate (DCA) could reduce this alteration, preventing proliferation through the reactivation of aerobic metabolism in lung adenocarcinoma cell line (A549). A549 cells were cultured in a hypoxic chamber at 1% O2 for 72 hours to determine the effect of this combination on growth, migration, and expression of hypoxia-inducible factors (HIFs) by immunofluorescence. The effect in the metabolism was evaluated by the determination of glucose/glutamine consumption and the lactate/glutamate production. The treatment of 2-ME (10 μM) in combination with DCA (40 mM) under hypoxic conditions showed an inhibitory effect on growth and migration. Notably, this reduction could be attributed to 2-ME, while DCA had a predominant effect on metabolic activity. Moreover, this combination decreases the signaling of HIF-3α and partially HIF-1α but not HIF-2α. The results of this study highlight the antitumor activity of the combination of 2-ME 10 μl/DCA 40 mM, even in hypoxic conditions.
Copyright © 2020 Yair Romero et al.
MeSH terms
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2-Methoxyestradiol / pharmacology
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2-Methoxyestradiol / therapeutic use*
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A549 Cells
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Antineoplastic Agents / pharmacology*
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Antineoplastic Combined Chemotherapy Protocols / pharmacology
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Antineoplastic Combined Chemotherapy Protocols / therapeutic use*
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Apoptosis Regulatory Proteins / metabolism
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Basic Helix-Loop-Helix Transcription Factors / metabolism
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Carcinoma, Non-Small-Cell Lung / drug therapy*
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Carcinoma, Non-Small-Cell Lung / pathology
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Cell Movement / drug effects
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Cell Proliferation / drug effects
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Dichloroacetic Acid / pharmacology
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Dichloroacetic Acid / therapeutic use*
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Glucose / metabolism
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Glutamic Acid / metabolism
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Glutamine / metabolism
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Glycolysis / drug effects
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Humans
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Hypoxia-Inducible Factor 1, alpha Subunit / metabolism
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Lactic Acid / metabolism
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Lung Neoplasms / drug therapy*
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Lung Neoplasms / pathology
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Repressor Proteins / metabolism
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Signal Transduction / drug effects
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Tumor Hypoxia* / drug effects
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Tumor Microenvironment* / drug effects
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Wound Healing / drug effects
Substances
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Antineoplastic Agents
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Apoptosis Regulatory Proteins
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Basic Helix-Loop-Helix Transcription Factors
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HIF3A protein, human
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Hypoxia-Inducible Factor 1, alpha Subunit
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Repressor Proteins
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Glutamine
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endothelial PAS domain-containing protein 1
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Lactic Acid
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Glutamic Acid
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2-Methoxyestradiol
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Dichloroacetic Acid
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Glucose