Selective Killing of Adriamycin-Resistant (G2 Checkpoint-Deficient and MRP1-Expressing) Cancer Cells by Docetaxel

Demidenko, Zoya N.; Halicka, Dorota; Kunicki, Jan; McCubrey, James A.; Darzynkiewicz, Zbigniew; Blagosklonny, Mikhail V.

doi:10.1158/0008-5472.can-04-4428

Cited by 20 publications

(20 citation statements)

References 43 publications

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“…Similar approach has been used in various studies to derive drug-resistant cells starting with parental sensitive cells. HL60 cells resistant to vincristine [27,28], to adriamycin [29] and to melphalan [30] were generated to investigate the resistance mechanisms and to reverse the MDR.…”

Section: Discussionmentioning

confidence: 99%

Upregulation of multi drug resistance genes in doxorubicin resistant human acute myelogeneous leukemia cells and reversal of the resistance

et al. 2007

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The major problem in the treatment of acute myeloid leukemia (AML) patients results from multidrug resistance to administered anticancer agents. Drug resistance proteins, MDR1 and MRP1, which work as drug efflux pumps, can mediate the multidrug resistance of human leukemia cells. In this study, the mechanisms of resistance to doxorubicin-induced cell death in human HL60 AML cells were examined.Continuous exposure of cells to step-wise increasing concentrations of doxorubicin resulted in the selection of HL60/DOX cells, which expressed about 10.7-fold resistance as compared to parental sensitive cells. The expression analyses of MRP1 and MDR1 drug efflux proteins in doxorubicin-sensitive and -resistant HL60 cells revealed that there was an upregulation of MRP1 gene in HL60/DOX cells as compared to parental sensitive cells. On the other hand, while there was no expression of MDR1 gene in parental cells, the expression of MDR1 gene was upregulated in HL60/DOX cells. HL60/DOX cells also showed cross-resistance to cytosine arabinoside (Ara-c). This resistance was reversed by a combination therapy of Ara-c and cyclosporine A. However, the expression levels of CD15 and CD16 surface markers were significantly decreased in HL60/DOX cells.

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Section: Discussionmentioning

confidence: 99%

Upregulation of multi drug resistance genes in doxorubicin resistant human acute myelogeneous leukemia cells and reversal of the resistance

et al. 2007

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“…8F) (20). 1KO cells, however, were markedly deficient in both G 1 and G 2 arrest after the identical doxorubicin treatment conditions and appeared to accumulate primarily in S phase (Fig.…”

Section: Effects Of 5-azadc On Dnmt Protein Levels and Cell Growthmentioning

confidence: 95%

DNA Methylation Inhibitor 5-Aza-2′-Deoxycytidine Induces Reversible Genome-Wide DNA Damage That Is Distinctly Influenced by DNA Methyltransferases 1 and 3B

Palii

Emburgh

Sankpal

et al. 2008

Molecular and Cellular Biology

334

301

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Genome-wide DNA methylation patterns are frequently deregulated in cancer. There is considerable interest in targeting the methylation machinery in tumor cells using nucleoside analogs of cytosine, such as 5-aza-2-deoxycytidine (5-azadC). 5-azadC exerts its antitumor effects by reactivation of aberrantly hypermethylated growth regulatory genes and cytoxicity resulting from DNA damage. We sought to better characterize the DNA damage response of tumor cells to 5-azadC and the role of DNA methyltransferases 1 and 3B (DNMT1 and DNMT3B, respectively) in modulating this process. We demonstrate that 5-azadC treatment results in growth inhibition and G 2 arrest-hallmarks of a DNA damage response. 5-azadC treatment led to formation of DNA double-strand breaks, as monitored by formation of ␥-H2AX foci and comet assay, in an ATM (ataxiatelangiectasia mutated)-dependent manner, and this damage was repaired following drug removal. Further analysis revealed activation of key strand break repair proteins including ATM, ATR (ATM-Rad3-related), checkpoint kinase 1 (CHK1), BRCA1, NBS1, and RAD51 by Western blotting and immunofluorescence. Significantly, DNMT1-deficient cells demonstrated profound defects in these responses, including complete lack of ␥-H2AX induction and blunted p53 and CHK1 activation, while DNMT3B-deficient cells generally showed mild defects. We identified a novel interaction between DNMT1 and checkpoint kinase CHK1 and showed that the defective damage response in DNMT1-deficient cells is at least in part due to altered CHK1 subcellular localization. This study therefore greatly enhances our understanding of the mechanisms underlying 5-azadC cytotoxicity and reveals novel functions for DNMT1 as a component of the cellular response to DNA damage, which may help optimize patient responses to this agent in the future.DNA methylation is an essential epigenetic modification required for normal mammalian development, gene regulation, genomic imprinting, and chromatin structure (9). Methylation occurs at the C-5 position of cytosine within the CpG dinucleotide and is carried out by a family of DNA methyltransferases (DNMTs), DNMT1, DNMT3A, and DNMT3B (32). DNMT1 acts primarily as a maintenance methyltransferase by copying existing methylation patterns following DNA replication (53). DNMT3A and DNMT3B exhibit de novo methyltransferase activity and are required for establishing new methylation patterns during embryonic development (72). Deregulation of the DNA methylation machinery has been identified in several disease states, particularly cancer (78), and leads to global DNA hypomethylation of repetitive DNA, which has been linked to genomic instability (21) and, concomitantly, hypermethylation at the promoter regions of certain genes (tumor suppressors), leading to their aberrant silencing (43).The process of cytosine methylation is reversible and may be altered by biochemical and biological manipulation, making it an attractive target for therapeutic intervention. Demethylation and consequent reactivation of tumor ...

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“…For example, low concentrations of DOX (50 ng/ml), by arresting HL60 cells in G2, prevented apoptosis caused by PTX and docetaxel. 29 Here we compared cytoprotection caused by GA and low cytostatic concentrations of DOX (low DOX). Unlike GA, low DOX did not prevent cell death caused by high concentrations of DOX (Figure 11b).…”

Section: Comparison Of Three Types Of Cytoprotectionmentioning

confidence: 99%

Pharmacological induction of Hsp70 protects apoptosis-prone cells from doxorubicin: comparison with caspase-inhibitor- and cycle-arrest-mediated cytoprotection

Demidenko

Vivo²,

Halicka

et al. 2005

Cell Death Differ

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Selective modulation of cell death is important for rational chemotherapy. By depleting Hsp90-client oncoproteins, geldanamycin (GA) and 17-allylamino-17-demethoxy-GA (17-AAG) (heat-shock protein-90-active drugs) render certain oncoprotein-addictive cancer cells sensitive to chemotherapy. Here we investigated effects of GA and 17-AAG in apoptosis-prone cells such as HL60 and U937. In these cells, doxorubicin (DOX) caused rapid apoptsis, whereas GAinduced heat-shock protein-70 (Hsp70) (a potent inhibitor of apoptosis) and G1 arrest without significant apoptosis. GA blocked caspase activation and apoptosis and delayed cell death caused by DOX. Inhibitors of translation and transcription and siRNA Hsp70 abrogated cytoprotective effects of GA. Also GA failed to protect HL60 cells from cytotoxicity of actinomycin D and flavopiridol (FL), inhibitors of transcription. We next compared cytoprotection by GA-induced Hsp70, caspase inhibitors (Z-VAD-fmk) and cell-cycle arrest. Whereas cell-cycle arrest protected HL60 cells from paclitaxel (PTX) but not from FL and DOX, Z-VAD-fmk prevented FLinduced apoptosis but was less effective against DOX and PTX. Thus, by inducing Hsp70, GA protected apoptosis-prone cells in unique and cell-type selective manner. Since GA does not protect apoptosis-reluctant cancer cells, we envision a therapeutic strategy to decrease side effects of chemotherapy without affecting its therapeutic efficacy.

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Selective Killing of Adriamycin-Resistant (G2 Checkpoint-Deficient and MRP1-Expressing) Cancer Cells by Docetaxel

Cited by 20 publications

References 43 publications

Upregulation of multi drug resistance genes in doxorubicin resistant human acute myelogeneous leukemia cells and reversal of the resistance

Upregulation of multi drug resistance genes in doxorubicin resistant human acute myelogeneous leukemia cells and reversal of the resistance

DNA Methylation Inhibitor 5-Aza-2′-Deoxycytidine Induces Reversible Genome-Wide DNA Damage That Is Distinctly Influenced by DNA Methyltransferases 1 and 3B

Pharmacological induction of Hsp70 protects apoptosis-prone cells from doxorubicin: comparison with caspase-inhibitor- and cycle-arrest-mediated cytoprotection

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