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

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.

• Authors: Yair Romero, Manuel Castillejos-López, Susana Romero-García, Alfonso Salgado Aguayo, Iliana Herrera, Misael O Garcia-Martin, Luz Maria Torres-Espíndola, Maria Cristina Negrete-García, Angel Camarena Olvera, Juan Carlos Huerta-Cruz, Rafael Velazquez Cruz, José Cisneros, Edgar Flores Soto, Héctor Solís-Chagoyán, Criselda Mendoza-Milla, Carlos Cabello-Gutiérrez, Víctor Ruiz, Arnoldo Aquino-Gálvez
• Journal: Oxidative medicine and cellular longevity (Oxid Med Cell Longev) Vol. 2020 Pg. 3176375 ( 2020) ISSN: 1942-0994 [Electronic] United States
• PMID: 33149807 (Publication Type: Journal Article)
• Copyright: Copyright © 2020 Yair Romero et al.

Chemical References

• 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

Topics

• 2-Methoxyestradiol (pharmacology, therapeutic use)
• A549 Cells
• Antineoplastic Agents (pharmacology)
• Antineoplastic Combined Chemotherapy Protocols (pharmacology, therapeutic use)
• Apoptosis Regulatory Proteins (metabolism)
• Basic Helix-Loop-Helix Transcription Factors (metabolism)
• Carcinoma, Non-Small-Cell Lung (drug therapy, pathology)
• Cell Movement (drug effects)
• Cell Proliferation (drug effects)
• Dichloroacetic Acid (pharmacology, 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, pathology)
• Repressor Proteins (metabolism)
• Signal Transduction (drug effects)
• Tumor Hypoxia (drug effects)
• Tumor Microenvironment (drug effects)
• Wound Healing (drug effects)