Acute myeloid leukemia cells MOLM-13 and SKM-1 established for resistance by azacytidine are crossresistant to P-glycoprotein substrates

• Published in: Toxicology in vitro 2015-10, Vol.29 (7), p.1405-1415
• Main Authors: Messingerova, Lucia, Imrichova, Denisa, Kavcova, Helena, Turakova, Katarina, Breier, Albert, Sulova, Zdena
• Format: Article
• Language: English
• Subjects: AML cell lines SKM-1 and MOLM-13; Antineoplastic Agents - pharmacology; Apoptosis - drug effects; Apoptosis regulators; ATP Binding Cassette Transporter, Sub-Family B - genetics; ATP Binding Cassette Transporter, Sub-Family G, Member 2; ATP-Binding Cassette Transporters - genetics; Azacitidine - pharmacology; bcl-2-Associated X Protein - metabolism; Cell Line, Tumor; Cisplatin - pharmacology; Doxorubicin - pharmacology; Drug resistance; Drug Resistance, Neoplasm; Glutathione S-transferase; Glutathione Transferase - metabolism; Humans; Leukemia, Myeloid, Acute - metabolism; Mitoxantrone - pharmacology; Multidrug Resistance-Associated Proteins - genetics; Neoplasm Proteins - genetics; NF-kappa B p50 Subunit - genetics; NF-kappa B p52 Subunit - genetics; NF-κB; P-glycoprotein; Proto-Oncogene Proteins c-bcl-2 - metabolism; Transcription Factor RelA - genetics; Tumor Suppressor Protein p53 - metabolism; Vincristine - pharmacology
• ISSN: 0887-2333; 1879-3177
• DOI: 10.1016/j.tiv.2015.05.011

•Multidrug resistant SKM-1 and MOLM-13 cell variants by selection with azacytidine were established.•Induction of P-glycoprotein and glutathione S-transferase in resistant cell variants were proved.•Altered expressions of antiapoptotic and proapoptotic proteins in resistant variant of cells were observed.•Resistant variants of SKM-1 and MOLM-13 cells exert depressed sensitivity to AzaC and P-gp substrates. 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.