APVV-0290-10

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Alternation in cell metabolism asocciated with drug transporter P-glycoprotein overexpression in leukemia cells       

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Principal investigator: Zdena Sulová

Duration: May 2011 – October 2014

Coordinating institution: Institute of Molecular Physiology and Genetics, SAS, Bratislava

Annotation:

Multidrug resistance (MDR) of neoplastic cells represent real obstacle in chemotherapy of cancer. Overexpression of membrane protein described as P-glycoprotein (Pgp) represents most often-observed molecular cause of MDR and take place after influence of cytotoxic agents – Pgp substrates on neoplastic cells. We applied the adaptation on vincristine (VCR) in development of L1210/VCR cell subline that exerts besides MDR phenotype several following alterations in phenotype: changes in spectrum of cell surface saccharides, changes in intracellular calcium homeostasis, changes in intracellulars levels of regulatory proteins like stress kinases or nuclear receptors for retinoids. These changes represents mostly pronounced differences between L1210 and L1210/VCR cells and could be induced by adaptation process not directly connected with Pgp expression. Another possibility is that they are directly linked with expression of Pgp in adapted cells as secondary cellular response. To resolve this question we have to compare cells, in which Pgp overexpression was induced by adaptation on drugs with cells overexpressing Pgp due to application of DNA recombination techniques. Therefore, we prepared L1210/T cell sublines that overexpress Pgp due to stable transfection with gene encoding human Pgp. Comparison of L1210/VCR and L1210/T cells from the points of described phenotype changes represent the aim of annotated project.

Keywords:

P-glycoprotein, leukemia, multidrug resistance, secondary cellular response, apoptosis, stress kinases, nuclear receptors

Objectives:

Study of changes in courses of important regulatory pathway that were directly associated with P-gp expression in leukemia cells represent the aim of annotated project. We plan to study the changes: in saccharide metabolism; in apoptosis induced by substances that are untransportable by P-gp; in protein kinase pathway namely involved in adaptation on different stress; in levels and activity of metaloproteinases and in levels and function of nuclear receptors.

Publications:
PubMed Breier A, Imrichova D, Paulikova H, Barancik M, Sulova Z: Vincristine as an inductor of drug resistance marker expression in neoplastic cells. In Vincristine: Clinical Uses, Pharmacokinetics and Impacts on Health, (Coello, J. M.; Sabres, Y. D., eds.) NOVA Science Publishers, 2013, pp 1-31
pdf Sulova Z, Brtko J, Macejová D, Breier A: Are Nuclear Receptors for Retinoids Involved in the Control of the Expression and Activity of P-Glycoprotein? In Retinoic Acid: Structure, Mechanisms and Roles in Disease (Cheng, L.H., It, Y. eds.) NOVA Publisher, 2012 pp. 29-52.
Breier A, Gibalova L, Seres M, Barancik M, Sulova Z: P-glycoprotein mediated multidrug resistance of cancer tissue: Implication for cancer chemotherapy. ISBN 978-80-89233-55-7, PETRUS Publisher, 2012
PubMed Messingerova L, Imrichova D, Kavcova H, Turakova K, Breier A, Sulova Z. Acute myeloid leukemia cells MOLM-13 and SKM-1 established for resistance by azacytidine are crossresistant to P-glycoprotein substrates. Toxicol In Vitro. 29 (2015) 1405-15.
PubMed Imrichova D, Messingerova L, Seres M, Kavcova H, Pavlikova L, Coculova M, Breier A, Sulova Z. 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. Eur J Pharm Sci. 77 (2015):29-39.
PubMed Messingerova L, Jonasova A, Barancik M, Polekova L, Seres M, Gibalova L, Breier A, Sulova Z. Lenalidomide treatment induced the normalization of marker protein levels in blood plasma of patients with 5q-myelodysplastic syndrome. Gen Physiol Biophys. 34 (2015) 399–406
PubMed Turakova K, Pavlikova L, Messingerova L, Lakatos B, Breier A, Sulova Z. Reduced udp-glucose levels are associated with p-glycoprotein over-expression in l1210 cells and limit glucosylceramide synthase activity Anticancer Research 35 (2015) 2627-2634
PubMed Breier A, Stetka J, Bohacova V, Macejova D, Brtko J, Sulova Z. Effect of 9-cis retinoic acid and all-trans retinoic acid in combination with verapamil on P-glycoprotein expression in L1210 cells. Neoplasma. 61 (2014) 553-565
PubMed Imrichova D, Coculova M, Messingerova L, Sulova Z, Breier A. Vincristine-induced expression of P-glycoprotein in MOLM-13 and SKM-1 acute myeloid leukemia cell lines is associated with coexpression of nestin transcript. Gen Physiol Biophys. 33 (2014) 425-431.
PubMed Breier A, Gibalova L, Seres M, Barancik M, Sulova Z. New insight into p-glycoprotein as a drug target. Anti-cancer Agents Med Chem. 13 (2013) 159-70. (IF2012=2.610)
PubMed Barancik M, Bohacova V, Gibalova L, Sedlak J, Sulova Z, Breier A. Potentiation of Anticancer Drugs: Effects of Pentoxifylline on Neoplastic Cells. Int. J. Mol. Sci. 13 (2012) 369-382
 
PubMed Bubencíkova T, Cholujová D, Messingerová L, Mislovicova D, Seres M, Breier A, Sulova Z. Detection of glycomic alterations induced by overexpression of p-glycoprotein on the surfaces of l1210 cells using sialic Acid binding lectins. Int J Mol Sci. 13, (2012) 15177-15192
 
PubMed Gibalová L, Sereš M, Rusnák A, Ditte P, Labudová M, Uhrík B, Pastorek J, Sedlák J, Breier A, Sulová Z. P-glycoprotein depresses cisplatin sensitivity in L1210 cells by inhibiting cisplatin-induced caspase-3 activation. Toxicol In Vitro. 26 (2012) 435-444. (IF2012=2.650)
PubMed Šereš M, Cholujová D, Bubenčíkova T, Breier A, Sulová Z. Tunicamycin depresses p-glycoprotein glycosylation without an effect on its membrane localization and drug efflux activity in l1210 cells. Int J Mol Sci. 12 (2011) 7772-7784. (IF2012=2.464)