Chloroquine sensitizes MDA-MB-231 cells to osimertinib through autophagy–apoptosis crosstalk pathway
Identifieur interne : 000959 ( Main/Exploration ); précédent : 000958; suivant : 000960Chloroquine sensitizes MDA-MB-231 cells to osimertinib through autophagy–apoptosis crosstalk pathway
Auteurs : Brett Fleisher [États-Unis] ; Hardik Mody [États-Unis] ; Carolin Werkman [États-Unis] ; Sihem Ait-Oudhia [États-Unis]Source :
- Breast Cancer : Targets and Therapy [ 1179-1314 ] ; 2019.
Abstract
Url:
DOI: 10.2147/BCTT.S211030
PubMed: 31839713
PubMed Central: 6664863
Affiliations:
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,<addr-line>FL</addr-line>
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<sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Chloroquine sensitizes MDA-MB-231 cells to osimertinib through autophagy–apoptosis crosstalk pathway</title>
<author><name sortKey="Fleisher, Brett" sort="Fleisher, Brett" uniqKey="Fleisher B" first="Brett" last="Fleisher">Brett Fleisher</name>
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,<addr-line>Orlando</addr-line>
,<addr-line>FL</addr-line>
,<country>USA</country>
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<country xml:lang="fr">États-Unis</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
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<author><name sortKey="Mody, Hardik" sort="Mody, Hardik" uniqKey="Mody H" first="Hardik" last="Mody">Hardik Mody</name>
<affiliation wicri:level="1"><nlm:aff id="AFF0001"><institution>Center for Pharmacometrics and Systems Pharmacology, Department of Pharmaceutics, College of Pharmacy, University of Florida</institution>
,<addr-line>Orlando</addr-line>
,<addr-line>FL</addr-line>
,<country>USA</country>
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<country xml:lang="fr">États-Unis</country>
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<author><name sortKey="Werkman, Carolin" sort="Werkman, Carolin" uniqKey="Werkman C" first="Carolin" last="Werkman">Carolin Werkman</name>
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,<addr-line>Orlando</addr-line>
,<addr-line>FL</addr-line>
,<country>USA</country>
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<country xml:lang="fr">États-Unis</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
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<author><name sortKey="Ait Oudhia, Sihem" sort="Ait Oudhia, Sihem" uniqKey="Ait Oudhia S" first="Sihem" last="Ait-Oudhia">Sihem Ait-Oudhia</name>
<affiliation wicri:level="1"><nlm:aff id="AFF0001"><institution>Center for Pharmacometrics and Systems Pharmacology, Department of Pharmaceutics, College of Pharmacy, University of Florida</institution>
,<addr-line>Orlando</addr-line>
,<addr-line>FL</addr-line>
,<country>USA</country>
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<country xml:lang="fr">États-Unis</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
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<series><title level="j">Breast Cancer : Targets and Therapy</title>
<idno type="eISSN">1179-1314</idno>
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<front><div type="abstract" xml:lang="en"><p><bold>Background:</bold>
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.</p>
<p><bold>Purpose:</bold>
The EGFR is frequently overexpressed in TNBC, and the EGFR-overexpressing TNBC presumably escapes EGFR inhibitor therapy by upregulating autophagy and inhibiting apoptosis.</p>
<p><bold>Methods:</bold>
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<sup>®</sup>
after exposure to drugs. A synergistic interaction (CI <1) was identified with combinations of 4–6.5 μM osimertinib with 30–75 μM chloroquine.</p>
<p><bold>Results:</bold>
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.</p>
<p><bold>Conclusion:</bold>
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.</p>
</div>
</front>
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<affiliations><list><country><li>États-Unis</li>
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