Bcr–Abl-independent mechanism of resistance to imatinib in K562 cells: Induction of cyclooxygenase-2 (COX-2) by histone deacetylases (HDACs)

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 gr...

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Veröffentlicht in:	Leukemia research 2010-09, Vol.34 (9), p.1132-1138
Hauptverfasser:	Kalle, Arunasree M, Sachchidanand, Sachchidanand, Pallu, Reddanna
Format:	Artikel
Sprache:	eng
Schlagworte:	Antineoplastic Agents - pharmacology Apoptosis ATP Binding Cassette Transporter, Sub-Family B ATP-Binding Cassette, Sub-Family B, Member 1 - metabolism Base Sequence Bax Bcl2 Benzamides COX-2 CREB Cyclooxygenase 2 - genetics Cyclooxygenase 2 - metabolism DNA Primers Drug Resistance, Neoplasm Enzyme Activation Fusion Proteins, bcr-abl - metabolism Gene Knockdown Techniques HDACs Hematology, Oncology and Palliative Medicine Histone Deacetylases - metabolism Humans Imatinib Mesylate Imatinib-resistant K562 cells K562 Cells Leukemia, Erythroblastic, Acute - enzymology Leukemia, Erythroblastic, Acute - metabolism Leukemia, Erythroblastic, Acute - pathology MDR1 Piperazines - pharmacology Protein Kinase C - metabolism Pyrimidines - pharmacology Reverse Transcriptase Polymerase Chain Reaction RNA, Small Interfering
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Zusammenfassung:	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 PGE2 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 PGE2 –cAMP–PKC-mediated pathway.
ISSN:	0145-2126 1873-5835
DOI:	10.1016/j.leukres.2010.01.030