Antitumor Therapy under Hypoxic Microenvironment by the Combination of 2-Methoxyestradiol and Sodium Dichloroacetate on Human Non-Small-Cell Lung Cancer

Oxid Med Cell Longev. 2020 Oct 12:2020:3176375. doi: 10.1155/2020/3176375. eCollection 2020.

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.

MeSH terms

  • 2-Methoxyestradiol / pharmacology
  • 2-Methoxyestradiol / therapeutic use*
  • A549 Cells
  • Antineoplastic Agents / pharmacology*
  • Antineoplastic Combined Chemotherapy Protocols / pharmacology
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use*
  • Apoptosis Regulatory Proteins / metabolism
  • Basic Helix-Loop-Helix Transcription Factors / metabolism
  • Carcinoma, Non-Small-Cell Lung / drug therapy*
  • Carcinoma, Non-Small-Cell Lung / pathology
  • Cell Movement / drug effects
  • Cell Proliferation / drug effects
  • Dichloroacetic Acid / pharmacology
  • Dichloroacetic Acid / therapeutic use*
  • Glucose / metabolism
  • Glutamic Acid / metabolism
  • Glutamine / metabolism
  • Glycolysis / drug effects
  • Humans
  • Hypoxia-Inducible Factor 1, alpha Subunit / metabolism
  • Lactic Acid / metabolism
  • Lung Neoplasms / drug therapy*
  • Lung Neoplasms / pathology
  • Repressor Proteins / metabolism
  • Signal Transduction / drug effects
  • Tumor Hypoxia* / drug effects
  • Tumor Microenvironment* / drug effects
  • Wound Healing / drug effects

Substances

  • Antineoplastic Agents
  • Apoptosis Regulatory Proteins
  • Basic Helix-Loop-Helix Transcription Factors
  • HIF3A protein, human
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Repressor Proteins
  • Glutamine
  • endothelial PAS domain-containing protein 1
  • Lactic Acid
  • Glutamic Acid
  • 2-Methoxyestradiol
  • Dichloroacetic Acid
  • Glucose