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Rapid Induction of P-Glycoprotein mRNA and Protein Expression by Cytarabine in HL-60 Cells
Örebro universitet, Hälsoakademin.
Karolinska Institutet.
Örebro universitet, Hälsoakademin.
Örebro universitet, Hälsoakademin.
Vise andre og tillknytning
2009 (engelsk)Inngår i: Anticancer Research, ISSN 0250-7005, E-ISSN 1791-7530, Vol. 29, nr 10, s. 4071-4076Artikkel i tidsskrift (Fagfellevurdert) 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.

sted, utgiver, år, opplag, sider
Athens: International Institute of Anticancer Research, 2009. Vol. 29, nr 10, s. 4071-4076
Emneord [en]
Drug resistance, P-glycoprotein, daunorubicin, cytarabine, HL-60 cells, glutathione-S-transferase pi
HSV kategori
Forskningsprogram
Biomedicin
Identifikatorer
URN: urn:nbn:se:oru:diva-10580ISI: 000271487400051PubMedID: 19846953Scopus ID: 2-s2.0-71949122848OAI: oai:DiVA.org:oru-10580DiVA, id: diva2:317294
Tilgjengelig fra: 2010-05-03 Laget: 2010-05-03 Sist oppdatert: 2017-12-12bibliografisk kontrollert
Inngår i avhandling
1. On mechanisms of drug resistance in acute myeloid leukemia
Åpne denne publikasjonen i ny fane eller vindu >>On mechanisms of drug resistance in acute myeloid leukemia
2010 (engelsk)Doktoravhandling, med artikler (Annet vitenskapelig)
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.

sted, utgiver, år, opplag, sider
Örebro: Örebro universitet, 2010. s. 87
Serie
Örebro Studies in Medicine, ISSN 1652-4063 ; 45
HSV kategori
Forskningsprogram
Biomedicin
Identifikatorer
urn:nbn:se:oru:diva-10603 (URN)978-91-7668-729-1 (ISBN)
Disputas
2010-06-04, Wilandersalen, Universitetssjukhuset, Örebro, 15:54 (svensk)
Opponent
Veileder
Tilgjengelig fra: 2010-05-05 Laget: 2010-05-04 Sist oppdatert: 2018-11-09bibliografisk kontrollert

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