Abstract
The goal of this study was to investigate the role of the ABC transporters in the evolution of tumor cell populations treated with bortezomib. Bortezomib (PS-341, Velcade) is a proteasome inhibitor used for treatment of some malignancies. Several pairs of cell lines different in Pgp expression (P-glycoprotein transporter, ABCB1) have been used in the study. We showed that the influence of the Pgp hyperexpression on cell sensitivity to bortezomib was bidirectional and depended on the tissue type. Bortezomib changed the mRNA level of MDR1 (ABCB1 and MRP1 (ABCC1)) genes, suggesting that the proteasome inhibitor is able to decrease the activity of some regulators of genes/proteins implicated in MDR. Bortezomib treatment increased the levels of proteins (Pgp or MPR1) in 3 out of 4 cell populations studied. Pgp was shown to remain functionally active in the cells cultured in bortezamib-containing medium. The UIC2-shift assay has shown that bortezomib is able to activate Pgp. This means that bortezomib influences Pgp conformation, thus activating the protein (in K562/i-S9 cells). These experiments also demonstrate that bortezomib is Pgp substrate.
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References
Glavinas, H., Krajcsi, P., Cserepes, J., and Sarkadi, B., The Role of ABC Transporters in Drug Resistance, Metabolism and Toxicity, Curr. Drug Delivery, 2004, vol. 1, pp. 27–42.
Stavrovskaya, A.A., Cellular Mechanisms of Multidrug Resistance of Tumor Cells, Biokhimia (Rus.), 2000, vol.65, pp. 95–106.
Higgins, C.F., Multiple Molecular Mechanisms for Multidrug Resistance Transporters, Nature, 2007, vol. 446, pp. 749–757.
Stromskaya, T.P, Rybalkina, E.Y, Kruglov, S.S, Zabotina, T.N, Mechetner, E.B, Turkina, A.G., and Stavrovskaya, A.A., Role of P-Glycoprotein in Evolution of Populations of Chronic Myeloid Leukemia Cells Treated with Imatinib, Biokhimia (Rus.), 2008, vol. 73, pp. 29–37.
Richardson, P.G., Hideshima, T., and Anderson, K.C., Bortezomib (PS-341): A Novel, First-in-Class Proteasome Inhibitor for the Treatment of Multiple Myeloma and Other Cancers, Cancer Control., 2003, vol. 10, pp. 361–369.
Styczynski, J., Olszewska-Slonina, D., Kolodziej, B., Napieraj, M., and Wysocki, M., Activity of Bortezomib in Glioblastoma, Anticancer Res., 2006, vol. 26, pp. 4499–4503.
Nakamura, T., Tanaka, K., Matsunobu, T., Okada, T., Nakatani, F., Sakimura, R., Hanada, M., and Iwamoto, Y., The Mechanism of Cross-Resistance to Proteasome Inhibitor Bortezomib and Overcoming Resistance in Ewing’s Family Tumor Cells, Int. J. Oncol., 2007, vol. 31, pp. 803–811.
Minderman, H., Zhou, Y., O’Loughlin, K.L., and Baer, M.R., Bortezomib Activity and in vitro Interactions with Anthracyclines and Cytarabine in Acute Myeloid Leukemia Cells Are Independent of Multidrug Resistance Mechanisms and P53 Status, Cancer Chemother. Pharmacol., 2007, vol. 60, pp. 245–255.
Rumpold, H., Salvador, C., Wolf, A.M., Tilg, H., Gastl, G., and Wolf, D., Knockdown of Pgp Resensitizes Leukemic Cells to Proteasome Inhibitors, Biochem. Biophys. Res. Commun., 2007, vol. 21, pp. 549–554.
Lozzio, B.B. and Lozzio, C.B., Properties and Usefulness of the Original K-562 Human Myelogenous Leukemia Cell Line, Leuk. Res., 1979, vol. 3, pp. 363–370.
Mechetner, E.B. and Roninson, I.B., Efficient Inhibition of P-Glycoprotein-Mediated Multidrug Resistance with a Monoclonal, Proc. Natl. Acad. Sci. USA, 1992, vol. 89, pp. 5824–5828.
Koeffler, H.P. and Golde, D.W., Acute Myelogenous Leukemia: A Human Cell Line Responsive to Colony-Stimulating Activity, Science, 1978, vol. 200, pp. 1153–1154.
Akiyama, S., Fojo, A., Hanover, J.A., Pastan, I., and Gottesman, M.M., Isolation and Genetic Characterization of Human KB Cell Lines Resistant to Multiple Drugs, Somat. Cell Mol. Genet., 1985, vol. 11, pp. 117–126.
Sherbakova, E.A, Stromskaia, T.P, Rybalkina, E.Yu., Kalita, O.V., and Stavrovskaia, A.A., Role of PTEN Protein in Multidrug Resistance of Prostate Cancer Cells, Molek. Biologia (Rus.), 2008, vol. 42, pp. 430–435.
Park, S.W., Lomri, N., Simeoni, L.A., Fruehauf, J.P., and Mechetner, E., Analysis of P-Glycoprotein-Mediated Membrane Transport in Human Peripheral Blood Lymphocytes Using the UIC2 Shift Assay, Cytometry A, 2003, vol. 53, pp. 67–78.
Vaiman, A.V., Stromskaya, T.P., Rybalkina, E.Y, Sorokin, A.V., Ovchinnikov, L.P., Stavrovskaya A.A. Development of Drug Resistance in the Population of Colon Cancer Cells under the Effect of Multifunctional Protein YB-1, Bull. Exp. Biol. Med., 2007, vol. 143, pp. 463–466.
Stromskaya, T.P., Rybalkina, E.Y., Zabotina, T.N., Shishkin, A.A., and Stavrovskaya, A.A., Influence of RARα Gene on MDR1 Expression and P-Glycoprotein Function in Human Leukemic Cells, Cancer Cell Internat., 2005, vol. 5, pp. 5–15.
Yerlikaya, A. and Erin, N., Differential Sensitivity of Breast Cancer and Melanoma Cells to Proteasome Inhibitor Velcade, Int. J. Mol. Med., 2008, vol. 22, pp. 817–823.
Sorokin, A.V., Selyutina, A.A., Skabkin, M.A., and Guryanov, S.G., Proteasome-Mediated Cleavage of the Y-Box-Binding Protein 1 Is Linked to DNA-Damage Stress Response, EMBO J., 2005, vol. 24, pp. 3602–3612.
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Original Russian Text © L.A. Panischeva, E.S. Kakpakova, E.Y. Rybalkina, A.A. Stavrovskaya, 2010, published in Biologicheskie Membrany, 2010, Vol. 27, No. 2, pp. 195–201.
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Panischeva, L.A., Kakpakova, E.S., Rybalkina, E.Y. et al. The influence of proteasome inhibitor bortezamib on ABC transporters’ expression and activity in tumor cells. Biochem. Moscow Suppl. Ser. A 4, 220–225 (2010). https://doi.org/10.1134/S1990747810020145
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DOI: https://doi.org/10.1134/S1990747810020145