title: Acute myeloid leukemia cells MOLM-13 and SKM-1 established for resistance by azacytidine are crossresistant to P-glycoprotein substrates.
abstract: Establishment of the acute myeloid leukemia cells SKM-1 and MOLM-13 for resistance by azacytidine (AzaC) resulted in SKM-1/AzaC and MOLM-13/AzaC cell variants with reduced sensitivity to AzaC. Despite the fact that AzaC is not substrate of P-glycoprotein (P-gp), the adaptation procedure resulted in an induction in P-gp expression/efflux activity that confers crossresistance to P-gp substrates in both resistant cell variants. While the resistance to P-gp substrates in SKM-1/AzaC and MOLM-13/AzaC cells could be reversed by the P-gp inhibitors, resistance to AzaC was insensitive to these inhibitors in both resistant cell variants. In addition, NF-κB and the antiapoptotic protein Bcl-2 were downregulated and the proapoptotic proteins Bax and p53 were upregulated in both resistant cell variants when compared with their sensitive counterparts. Moreover, at least five times the elevation in overall glutathione S-transferase activity was measured with 1-chloro-2, 5-dinitrobenzene as a substrate in the resistant variant of both cell lines. Taken together, the findings of the present study indicate that the treatment of AML cells with AzaC might lead to a drug resistance phenotype that may be associated with cross resistance to P-gp substrates and substrates of glutathione S-transferases.
authors.affiliation: Institute of Molecular Physiology and Genetics, Slovak Academy of Sciences, Vlarska 5, 83334 Bratislava, Slovakia; Institute of Biochemistry, Nutrition and Health Protection, Faculty of Chemical and Food Technology, Slovak University of Technology, Radlinskeho 9, 812 37 Bratislava, Slovakia.
authors.forename: Lucia
authors.initials: L
authors.lastname: Messingerova
authors.affiliation: Institute of Molecular Physiology and Genetics, Slovak Academy of Sciences, Vlarska 5, 83334 Bratislava, Slovakia.
authors.forename: Denisa
authors.initials: D
authors.lastname: Imrichova
authors.affiliation: Institute of Molecular Physiology and Genetics, Slovak Academy of Sciences, Vlarska 5, 83334 Bratislava, Slovakia.
authors.forename: Helena
authors.initials: H
authors.lastname: Kavcova
authors.affiliation: Institute of Biochemistry, Nutrition and Health Protection, Faculty of Chemical and Food Technology, Slovak University of Technology, Radlinskeho 9, 812 37 Bratislava, Slovakia.
authors.forename: Katarina
authors.initials: K
authors.lastname: Turakova
authors.affiliation: Institute of Molecular Physiology and Genetics, Slovak Academy of Sciences, Vlarska 5, 83334 Bratislava, Slovakia; Institute of Biochemistry, Nutrition and Health Protection, Faculty of Chemical and Food Technology, Slovak University of Technology, Radlinskeho 9, 812 37 Bratislava, Slovakia. Electronic address: albert.breier@stuba.sk.
authors.forename: Albert
authors.initials: A
authors.lastname: Breier
authors.affiliation: Institute of Molecular Physiology and Genetics, Slovak Academy of Sciences, Vlarska 5, 83334 Bratislava, Slovakia.
authors.forename: Zdena
authors.initials: Z
authors.lastname: Sulova
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000235:genetics; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000235:genetics; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001374:Azacitidine / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000494:pharmacology; D004317:Doxorubicin / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm; D005982:Glutathione Transferase / Q000378:metabolism; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000378:metabolism; D008942:Mitoxantrone / Q000494:pharmacology; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000235:genetics; D052002:NF-kappa B p50 Subunit / Q000235:genetics; D052003:NF-kappa B p52 Subunit / Q000235:genetics; D009363:Neoplasm Proteins / Q000235:genetics; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D051996:Transcription Factor RelA / Q000235:genetics; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D014750:Vincristine / Q000494:pharmacology; D051028:bcl-2-Associated X Protein / Q000378:metabolism
chemical_list: D018435:ATP Binding Cassette Transporter, Subfamily B; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D000970:Antineoplastic Agents; D001374:Azacitidine; D002945:Cisplatin; D004317:Doxorubicin; D005982:Glutathione Transferase; D008942:Mitoxantrone; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D052002:NF-kappa B p50 Subunit; D052003:NF-kappa B p52 Subunit; D009363:Neoplasm Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D051996:Transcription Factor RelA; D016159:Tumor Suppressor Protein p53; D014750:Vincristine; D051028:bcl-2-Associated X Protein; C513055:ABCB1 protein, human; C116614:ABCG2 protein, human; C494826:BAX protein, human; C489548:NFKB1 protein, human; C498206:NFKB2 protein, human; C498143:RELA protein, human; C421109:multidrug resistance-associated protein 1
keywords: AML cell lines SKM-1 and MOLM-13; Apoptosis regulators; Drug resistance; Glutathione S-transferase; NF-κB; P-glycoprotein