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Rapid Induction of P-Glycoprotein mRNA and Protein Expression by Cytarabine in HL-60 Cells
Örebro University, School of Health and Medical Sciences.
Karolinska Institutet.
Örebro University, School of Health and Medical Sciences.
Örebro University, School of Health and Medical Sciences.
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2009 (English)In: Anticancer Research, ISSN 0250-7005, E-ISSN 1791-7530, Vol. 29, no 10, p. 4071-4076Article in journal (Refereed) Published
Abstract [en]

Background: Overexpression of P-glycoprotein (P-gp), breast cancer resistance protein (BCRP) and glutathione-S-transferase π (GSTπ) is associated with drug resistance in acute myeloid leukemia (AML). The short-term effects of drug exposure on their expression levels were investigated.

Materials and Methods: HL-60 cells and drug-resistant sublines were cultured with or without daunorubicin (DNR) and cytarabine (Ara-C). At several time-points the expression levels of P-gp, BCRP and GSTπ were determined.

Results: After exposure to Ara-C, P-gp mRNA rapidly increased in all the cell lines. P-gp protein was detected in the sensitive cells after 8 h exposure to Ara-C. GSTπ mRNA increased in the resistant cells, but no change in BCRP mRNA was observed. Exposure to DNR revealed rapidly increased P-gp and GSTπ mRNA in the resistant cells.

Conclusion: Ara-C rapidly increases P-gp mRNA and protein expression in sensitive and resistant cells, and GSTπ mRNA in resistant cells, in vitro. This may be of clinical importance during AML induction chemotherapy.

Place, publisher, year, edition, pages
Athens: International Institute of Anticancer Research, 2009. Vol. 29, no 10, p. 4071-4076
Keywords [en]
Drug resistance, P-glycoprotein, daunorubicin, cytarabine, HL-60 cells, glutathione-S-transferase pi
National Category
Medical and Health Sciences
Research subject
Biomedicine
Identifiers
URN: urn:nbn:se:oru:diva-10580ISI: 000271487400051PubMedID: 19846953Scopus ID: 2-s2.0-71949122848OAI: oai:DiVA.org:oru-10580DiVA, id: diva2:317294
Available from: 2010-05-03 Created: 2010-05-03 Last updated: 2017-12-12Bibliographically approved
In thesis
1. On mechanisms of drug resistance in acute myeloid leukemia
Open this publication in new window or tab >>On mechanisms of drug resistance in acute myeloid leukemia
2010 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

In this thesis focus has been to increase the knowledge and understanding of some of the mechanisms responsible for drug resistance in acute myeloid leukemia, as well as identify possibilities to predict drug resistance at diagnosis.

We have studied the intracellular behavior of cytostatic drugs and their main metabolites (paper I) and the cellular response to cytostatic drugs (paper III). A new flow cytometry in vitro chemosensitivity assay was developed, to enable identification of viable myeloid cells and determination of drug sensitivity (paper II). Finally, possible new markers involved in drug resistance were investigated (paper IV).

In conclusion we found that idarubicin and daunorubicin are equally toxic at the same intracellular concentrations. The contribution of the main metabolites to the cytotoxic effects of idarubicin and daunorubicin, in both drug sensitive and drug resistant human myeloid leukemia cells, is low. It is most likely the pharmacokinetic properties of idarubicin and daunorubicin that confer their main cytotoxic effect. With the new flow cytometry chemosensitivity assay we selectively identified viable CD13/CD33 expressing myeloid cells and found that the cytotoxicity results correlated to clinical parameters, such as secondary AML and resistant disease. Short-term exposure of leukemia cell lines with different levels of drug resistance to ara-C revealed that Pgp mRNA and protein ex-pression levels, as well as GSTπ mRNA levels, were rapidly up-regulated. Clinically, this up-regulation may be of importance for the sequential scheduling of daunorubicin and ara-C during the induction treatment of AML. CRIM1 has

never been studied in the context of drug resistance before. We show for the first time that baseline expression of CRIM1 mRNA is much higher in drug resistant leukemia cells compared to drug sensitive cells. We also found a co-variance between CRIM1 and Pgp mRNA expression levels in leukemia cell lines with different levels of drug resistance, suggesting that CRIM1 may be useful as a marker of drug resistance.

Place, publisher, year, edition, pages
Örebro: Örebro universitet, 2010. p. 87
Series
Örebro Studies in Medicine, ISSN 1652-4063 ; 45
National Category
Medical and Health Sciences
Research subject
Biomedicine
Identifiers
urn:nbn:se:oru:diva-10603 (URN)978-01-7668-729-1 (ISBN)
Public defence
2010-06-04, Wilandersalen, Universitetssjukhuset, Örebro, 15:54 (Swedish)
Opponent
Supervisors
Available from: 2010-05-05 Created: 2010-05-04 Last updated: 2017-10-18Bibliographically approved

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Prenkert, MalinUggla, BertilTina, ElisabetTidefelt, UlfStrid, Hilja

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