Abstract
Our previous studies have shown that overexpression of MDR1 and cyclooygenase-2 (COX-2) resulted in resistance development to imatinib in chronic myelogenous leukemia (CML) K562 (IR-K562) cells. In the present study, the regulatory mechanism of MDR1 induction by COX-2 was investigated. A gradual overexpression of MDR1 and COX-2 during the process of development was observed. Furthermore, down regulation of MDR1 upon COX-2 knockdown by siRNA showed a decrease in the PKC levels and activation of PKC by addition of PGE(2) to K562 cells, suggesting a role for PKC in the COX-2 mediated induction of MDR1. The present study demonstrates COX-2 induction by HDACs and MDR1 induction by COX-2 via PGE(2)-cAMP-PKC-mediated pathway.
Copyright 2010 Elsevier Ltd. All rights reserved.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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ATP Binding Cassette Transporter, Subfamily B
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ATP Binding Cassette Transporter, Subfamily B, Member 1 / metabolism
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Antineoplastic Agents / pharmacology*
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Apoptosis
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Base Sequence
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Benzamides
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Cyclooxygenase 2 / genetics
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Cyclooxygenase 2 / metabolism*
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DNA Primers
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Drug Resistance, Neoplasm
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Enzyme Activation
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Fusion Proteins, bcr-abl / metabolism*
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Gene Knockdown Techniques
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Histone Deacetylases / metabolism*
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Humans
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Imatinib Mesylate
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K562 Cells
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Leukemia, Erythroblastic, Acute / enzymology
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Leukemia, Erythroblastic, Acute / metabolism
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Leukemia, Erythroblastic, Acute / pathology
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Piperazines / pharmacology*
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Protein Kinase C / metabolism
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Pyrimidines / pharmacology*
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RNA, Small Interfering
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Reverse Transcriptase Polymerase Chain Reaction
Substances
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ABCB1 protein, human
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ATP Binding Cassette Transporter, Subfamily B
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ATP Binding Cassette Transporter, Subfamily B, Member 1
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Antineoplastic Agents
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Benzamides
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DNA Primers
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Piperazines
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Pyrimidines
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RNA, Small Interfering
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Imatinib Mesylate
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Cyclooxygenase 2
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Fusion Proteins, bcr-abl
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Protein Kinase C
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Histone Deacetylases