The Scientific Board of IMPG SAS evaluated as the most significant result of 2015 of application type the work by authors D. Imrichová, L. Messingerová, M. Šereš, H. Kavcová, L. Pavlíková, M. Cocuľová, K. Turáková, A. Jonášová, M. Barančík, L. Poleková, L. Gibalová, A. Breier, Z. Sulová:
Molecular mechanisms affecting treatment of AML and MDS.
Myelodysplastick syndrome (MDS) and acute myeloid leukemia (AML), which may develop from MDS, are characteristic by the presence of weakly differentited blood cells, the so called myeloblasts with surface expression of the CD33 marker, which is not present in normal blood stem cells and in non-myeloid tissue. Compounds with hypomethylation effect, e.g. azacytidine (AzaC), or with immunomodulatory effects, e.g. lenalidomide (LEN) may be effective in treatment of MDS and AML, but resistance to these drugs develops in some patients. Mechanisms of development of resistance to these drugs are not sufficiently understood. By repeated cultivation in media with increasing concentration of AzaC, LEN, mitoxantrone and vincristine we developed resistant variants of AML lines SKM-1 and MOLM-13 derived from patients, in which AML developed from MDS. Both cell lines showed phenotype of multidrug resistance upon selection pressure of the compounds, with a characteristic overexpression of P-glycoprotein (P-gp), glutathione S-transferase (GST), and surprisingly with redused expression of CD33 marker. This marker is used in targeting the therapy by humanized antibodies with bound drug. The results suggest that development of drug resistance in AML cells may lead not only to primary resistance against drugs used for therapy, but also to secondary resistance to substrates of P-gp a GST and to CD33-targeted immunotherapy.
Development of multidrug resistance in AML cells SKM-1 and MOLM-13 induced by drugs leads to development of resistance with a characteristic increase of P-gp and GST expression and with a decrease of CD33 expression. This leads to complex resistance to several chemotherapeutic procedures.
Projects: APVV-02-90-10, VEGA 2/0100/12, 2/0182/13, 2/0028/15, ITMS 26240220071.
Publication: IMRICHOVÁ, Denisa – MESSINGEROVÁ, Lucia – ŠEREŠ, Mário – KAVCOVÁ, Helena – PAVLÍKOVÁ, Lucia – COCUĽOVÁ, Martina – BREIER, Albert – SULOVÁ, Zdena. Selection of resistant acute myeloid leukemia SKM-1 and MOLM-13 cells by vincristine-, mitoxantrone- and lenalidomide-induced upregulation of P-glycoprotein activity and downregulation of CD33 cell surface exposure. In European Journal of Pharmaceutical Sciences, 2015, vol. 77, no., p. 29-39. (3.350 – IF2014). (2015 – Current Contents). ISSN 0928-0987.