Chloroquine sensitizes MDA-MB-231 cells to osimertinib through autophagy–apoptosis crosstalk pathway

Chloroquine sensitizes MDA-MB-231 cells to osimertinib through autophagy–apoptosis crosstalk pathway

Brett Fleisher, Hardik Mody, Carolin Werkman, Sihem Ait-OudhiaCenter for Pharmacometrics and Systems Pharmacology, Department of Pharmaceutics, College of Pharmacy, University of Florida, Orlando, FL, USABackground: Triple-negative breast cancer (TNBC) is a breast cancer that tests negative for estr...

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Autores principales: Fleisher B, Mody H, Werkman C, Ait-Oudhia S
Formato: article
Lenguaje:EN
Publicado: Dove Medical Press 2019
Materias:
EGFR Inhibitor
Drug-Drug interaction
Autophagic flux
programed cell death
Synergy
Neoplasms. Tumors. Oncology. Including cancer and carcinogens
RC254-282
Acceso en línea:https://doaj.org/article/d4abe8e9a9e04540a67106792fe88f36
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spelling oai:doaj.org-article:d4abe8e9a9e04540a67106792fe88f362021-12-02T08:01:21ZChloroquine sensitizes MDA-MB-231 cells to osimertinib through autophagy–apoptosis crosstalk pathway1179-1314https://doaj.org/article/d4abe8e9a9e04540a67106792fe88f362019-07-01T00:00:00Zhttps://www.dovepress.com/chloroquine-sensitizes-mda-mb-231-cells-to-osimertinib-through-autopha-peer-reviewed-article-BCTThttps://doaj.org/toc/1179-1314Brett Fleisher, Hardik Mody, Carolin Werkman, Sihem Ait-OudhiaCenter for Pharmacometrics and Systems Pharmacology, Department of Pharmaceutics, College of Pharmacy, University of Florida, Orlando, FL, USABackground: Triple-negative breast cancer (TNBC) is a breast cancer that tests negative for estrogen receptor (ER), progesterone receptors, and human epidermal growth factor receptors 2 (HER2). It is aggressive and invasive in nature and lacks targeted therapy.Purpose: The EGFR is frequently overexpressed in TNBC, and the EGFR-overexpressing TNBC presumably escapes EGFR inhibitor therapy by upregulating autophagy and inhibiting apoptosis.Methods: To parse the autophagy–apoptosis crosstalk pathway as a potential targeted therapy in TNBC, the activity of an EGFR inhibitor, osimertinib, alone and in combination with an autophagy inhibitor, chloroquine, was examined in EGFR-overexpressing TNBC cell line, MDA-MB-231. The nature of interaction between both drugs at various concentrations was determined by calculating combination indexes (CI) using CompuSyn software. Temporal changes in the expression of the autophagy marker, LC3B-II, and several apoptosis signaling molecules were measured using Western blot and luminex assay with MAGPIX®, after exposure to drugs. A synergistic interaction (CI <1) was identified with combinations of 4–6.5 μM osimertinib with 30–75 μM chloroquine.Results: A combination of osimertinib (6 μM) with chloroquine (30 μM) resulted in a 6-fold increase of LC3B-II relative to control compared to 2.5-fold increase for either drug alone. The caspase-3 expression increased 2-fold compared to a 0.5-fold decrease with chloroquine and 1.5-fold increase with osimertinib.Conclusion: Our results indicate that inhibition of the autophagic flux via chloroquine improves the effectiveness of osimertinib in TNBC cancer cells, warranting further investigations of this combination in vivo.Keywords: EGFR inhibitor, drug-drug interaction, autophagic flux, programed cell death, synergyFleisher BMody HWerkman CAit-Oudhia SDove Medical PressarticleEGFR InhibitorDrug-Drug interactionAutophagic fluxprogramed cell deathSynergyNeoplasms. Tumors. Oncology. Including cancer and carcinogensRC254-282ENBreast Cancer: Targets and Therapy, Vol Volume 11, Pp 231-241 (2019)
institution DOAJ
collection DOAJ
language EN
topic EGFR Inhibitor
Drug-Drug interaction
Autophagic flux
programed cell death
Synergy
Neoplasms. Tumors. Oncology. Including cancer and carcinogens
RC254-282
spellingShingle EGFR Inhibitor
Drug-Drug interaction
Autophagic flux
programed cell death
Synergy
Neoplasms. Tumors. Oncology. Including cancer and carcinogens
RC254-282
Fleisher B
Mody H
Werkman C
Ait-Oudhia S
Chloroquine sensitizes MDA-MB-231 cells to osimertinib through autophagy–apoptosis crosstalk pathway
description Brett Fleisher, Hardik Mody, Carolin Werkman, Sihem Ait-OudhiaCenter for Pharmacometrics and Systems Pharmacology, Department of Pharmaceutics, College of Pharmacy, University of Florida, Orlando, FL, USABackground: Triple-negative breast cancer (TNBC) is a breast cancer that tests negative for estrogen receptor (ER), progesterone receptors, and human epidermal growth factor receptors 2 (HER2). It is aggressive and invasive in nature and lacks targeted therapy.Purpose: The EGFR is frequently overexpressed in TNBC, and the EGFR-overexpressing TNBC presumably escapes EGFR inhibitor therapy by upregulating autophagy and inhibiting apoptosis.Methods: To parse the autophagy–apoptosis crosstalk pathway as a potential targeted therapy in TNBC, the activity of an EGFR inhibitor, osimertinib, alone and in combination with an autophagy inhibitor, chloroquine, was examined in EGFR-overexpressing TNBC cell line, MDA-MB-231. The nature of interaction between both drugs at various concentrations was determined by calculating combination indexes (CI) using CompuSyn software. Temporal changes in the expression of the autophagy marker, LC3B-II, and several apoptosis signaling molecules were measured using Western blot and luminex assay with MAGPIX®, after exposure to drugs. A synergistic interaction (CI <1) was identified with combinations of 4–6.5 μM osimertinib with 30–75 μM chloroquine.Results: A combination of osimertinib (6 μM) with chloroquine (30 μM) resulted in a 6-fold increase of LC3B-II relative to control compared to 2.5-fold increase for either drug alone. The caspase-3 expression increased 2-fold compared to a 0.5-fold decrease with chloroquine and 1.5-fold increase with osimertinib.Conclusion: Our results indicate that inhibition of the autophagic flux via chloroquine improves the effectiveness of osimertinib in TNBC cancer cells, warranting further investigations of this combination in vivo.Keywords: EGFR inhibitor, drug-drug interaction, autophagic flux, programed cell death, synergy
format article
author Fleisher B
Mody H
Werkman C
Ait-Oudhia S
author_facet Fleisher B
Mody H
Werkman C
Ait-Oudhia S
author_sort Fleisher B
title Chloroquine sensitizes MDA-MB-231 cells to osimertinib through autophagy–apoptosis crosstalk pathway
title_short Chloroquine sensitizes MDA-MB-231 cells to osimertinib through autophagy–apoptosis crosstalk pathway
title_full Chloroquine sensitizes MDA-MB-231 cells to osimertinib through autophagy–apoptosis crosstalk pathway
title_fullStr Chloroquine sensitizes MDA-MB-231 cells to osimertinib through autophagy–apoptosis crosstalk pathway
title_full_unstemmed Chloroquine sensitizes MDA-MB-231 cells to osimertinib through autophagy–apoptosis crosstalk pathway
title_sort chloroquine sensitizes mda-mb-231 cells to osimertinib through autophagy–apoptosis crosstalk pathway
publisher Dove Medical Press
publishDate 2019
url https://doaj.org/article/d4abe8e9a9e04540a67106792fe88f36
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AT modyh chloroquinesensitizesmdamb231cellstoosimertinibthroughautophagyndashapoptosiscrosstalkpathway
AT werkmanc chloroquinesensitizesmdamb231cellstoosimertinibthroughautophagyndashapoptosiscrosstalkpathway
AT aitoudhias chloroquinesensitizesmdamb231cellstoosimertinibthroughautophagyndashapoptosiscrosstalkpathway
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