Abstract
Aberrant DNA hypermethylation is critical in the regulation of renewal and maintenance of cancer stem cells (CSCs), which represent targets for carcinogenic initiation by chemical and environmental agents. The administration of decitabine (DAC), which is a DNA hypermethylation inhibitor, is an attractive approach to enhancing the chemotherapeutic response and overcoming drug resistance by CSCs. In this study, we investigated whether low-dose DAC encapsulated in nanoparticles could be used to sensitize bulk breast cancer cells and CSCs to chemotherapy. In vitro studies revealed that treatment with nanoparticles loaded with low-dose DAC (NPDAC) combined with nanoparticles loaded with doxorubicin (NPDOX) better reduced the proportion of CSCs with high aldehyde dehydrogenase activity (ALDH(hi)) in the mammospheres of MDA-MB-231 cells, and better overcame the drug resistance by ALDH(hi) cells. Subsequently, systemic delivery of NPDAC significantly down-regulated the expression of DNMT1 and DNMT3b in a MB-MDA-231 xenograft murine model and induced increased caspase-9 expression, which contributed to the increased sensitivity of the bulk cancer cells and CSCs to NPDOX treatment. Importantly, the combined treatment of NPDAC and NPDOX resulted in the lowest proportion of ALDH(hi) CSCs and the highest proportion of apoptotic tumor cells, and the best tumor suppressive effects in inhibiting breast cancer growth.
Keywords:
Cancer stem cell; Combination therapy; Decitabine; Doxorubicin; Drug delivery.
Copyright © 2014 Elsevier B.V. All rights reserved.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Aldehyde Dehydrogenase / genetics
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Aldehyde Dehydrogenase / metabolism
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Animals
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Antineoplastic Combined Chemotherapy Protocols / administration & dosage*
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Apoptosis / drug effects
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Azacitidine / administration & dosage
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Azacitidine / analogs & derivatives*
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Azacitidine / chemistry
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Breast Neoplasms / drug therapy*
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Breast Neoplasms / genetics
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Breast Neoplasms / metabolism
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Breast Neoplasms / pathology
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Caspase 9 / genetics
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Caspase 9 / metabolism
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Cell Line, Tumor
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Chemistry, Pharmaceutical
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DNA (Cytosine-5-)-Methyltransferase 1
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DNA (Cytosine-5-)-Methyltransferases / genetics
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DNA (Cytosine-5-)-Methyltransferases / metabolism
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DNA Methylation / drug effects
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DNA Methyltransferase 3B
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Decitabine
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Dose-Response Relationship, Drug
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Doxorubicin / administration & dosage*
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Doxorubicin / chemistry
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Drug Carriers*
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Drug Resistance, Neoplasm / drug effects*
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Drug Resistance, Neoplasm / genetics
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Epigenesis, Genetic / drug effects*
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Female
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Gene Expression Regulation, Neoplastic / drug effects
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Humans
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Mice, Inbred NOD
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Mice, SCID
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Nanomedicine
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Nanoparticles*
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Neoplastic Stem Cells / drug effects*
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Neoplastic Stem Cells / metabolism
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Neoplastic Stem Cells / pathology
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Polyesters / chemistry
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Polyethylene Glycols / chemistry
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Spheroids, Cellular
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Technology, Pharmaceutical / methods
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Time Factors
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Tumor Burden / drug effects
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Xenograft Model Antitumor Assays
Substances
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Drug Carriers
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Polyesters
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Polyethylene Glycols
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poly(lactide)
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Decitabine
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Doxorubicin
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Aldehyde Dehydrogenase
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DNA (Cytosine-5-)-Methyltransferase 1
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DNA (Cytosine-5-)-Methyltransferases
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DNMT1 protein, human
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Dnmt1 protein, mouse
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CASP9 protein, human
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Caspase 9
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Azacitidine