INCREASE OF DRUG RESISTANCE OF ACUTE MYELOID LEUKEMIA CELLS IN MULTICELLULAR AGGREGATES IN VITRO

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Abstract

Background: Therapeutic efficiency in treatment of acute myeloid leukemia (AML) ranges from 20 to 45%. One of the causes of the latter is a drug resistance acquired by leukemic cells under the influence of treatment with antitumor medicines. More important cause is a development of the primary resistance of myeloid leukemic cells to induction of cellular death associated with elemental microenvironment within the bone marrow. Studying primary resistance is very important, and first of all, to prevent development of drug resistance of leukemic cells and, correspondingly, to increase the efficiency of medicamental therapy. Aim: To study the mechanisms of primary resistance of AML cells to induction of cellular death. Materials and methods: Human AML cells of THP-1 line and mononuclear cells of the bone marrow were used in the study of patients with diagnosed AML. Multicellular aggregates were formed during cell cultivating on the 1.5% agarose. To cut off intercellular adhesion, the cells were cultivated in the medium with methylcellulose (0.9%). The viability of the cells was assessed by reduction of Alamar Blue indicator. Results: Within multicellular aggregates, about 75±5% of THP-1 cells were resistant to the activity of recombinant protein izTRAIL, 70±5% – to etoposide, and 40±7% – to sorafenib. Cutting off intercellular contacts decreased the resistance to them. Within multicellular aggregates of primary mononuclear cells, 45±5% of cells were resistant to sorafenib, 57±4% – to etoposide, and all cells were resistant to izTRAIL. Cutting off intracellular adhesion reduced the resistance to sorafenib and etoposide but not to izTRAIL. Conclusion: In multicellular aggregates, AML cells of THP-1 line and mononuclear cells of the bone marrow showed increased resistance to activity of recombinant protein izTRAIL, etoposide, and sorafenib. Diminishing intracellular adhesion in the medium including methylcellulose decreases cellular resistance to cytotoxic agents.

About the authors

S. G. Zakharov

Moscow Regional Research and Clinical Institute (MONIKI)

Author for correspondence.
Email: fake@neicon.ru
Russian Federation

A. K. Golenkov

Moscow Regional Research and Clinical Institute (MONIKI)

Email: fake@neicon.ru
Russian Federation

T. A. Mitina

Moscow Regional Research and Clinical Institute (MONIKI)

Email: fake@neicon.ru
Russian Federation

T. D. Lutskaya

Moscow Regional Research and Clinical Institute (MONIKI)

Email: fake@neicon.ru
Russian Federation

K. A. Belousov

Moscow Regional Research and Clinical Institute (MONIKI)

Email: fake@neicon.ru
Russian Federation

R. S. Fadeev

Institute of Theoretical and Experimental Biophysics of RAS

Email: fake@neicon.ru
Russian Federation

M. E. Solovieva

Institute of Theoretical and Experimental Biophysics of RAS

Email: fake@neicon.ru
Russian Federation

A. S. Senotov

Saratov Medical Centre of the FMBA of Russia

Email: fake@neicon.ru
Russian Federation

V. S. Akatov

Institute of Theoretical and Experimental Biophysics of RAS

Email: fake@neicon.ru
Russian Federation

References

  1. Hoffman R., Furie B., McGlave P., Silberstein L., Shattil S. Hematology: basic principles and practice. 4th ed. New York: Elsevier Churchill Livingstone; 2005.
  2. Marcucci G., Haferlach T., Döhner H. Molecular genetics of adult acute myeloid leukemia: prognostic and therapeutic implications. J Clin Oncol 2011;29(5):475-86.
  3. Matthews J.P., Bishop J.F., Young G.A., Juneja S.K., Lowenthal R.M., Garson O.M., Cobcroft R.G., Dodds A.J., Enno A., Gillett E.A., Hermann R.P., Joshua D.E., Ma D.D., Szer J., Taylor K.M., Wolf M., Bradstock K.F. Australian Leukemia Study Group. Patterns of failure with increasing intensification of induction chemotherapy for acute myeloid leukaemia. Br J Haematol 2001;113(3): 727-36.
  4. Sison E.A., Brown P. The bone marrow microenvironment and leukemia: biology and therapeutic targeting. Expert Rev Hematol 2011;4(3):271-83.
  5. Konopleva M., Andreeff M. Targeting the leukemia microenvironment. Curr Drug Targets 2007;8(6):685-701.
  6. Xu Q., Thompson J.E., Carroll M. mTOR regulates cell survival after etoposide treatment in primary AML cells. Blood 2005;106(13):4261-8.
  7. Xu Q., Simpson S.E., Scialla T.J., Bagg A., Carroll M. Survival of acute myeloid leukemia cells requires PI3 kinase activation. Blood 2003;102(3):972-80.
  8. Druker B.J., Tamura S., Buchdunger E., Ohno S., Segal G.M., Fanning S., Zimmermann J., Lydon N.B. Effects of a selective inhibitor of the Abl tyrosine kinase on the growth of Bcr-Abl positive cells. Nat Med 1996;2(5):561-6.
  9. Baxter E.J., Scott L.M., Campbell P.J., East C., Fourouclas N., Swanton S., Vassiliou G.S., Bench A.J., Boyd E.M., Curtin N., Scott M.A., Erber W.N., Green A.R. Cancer Genome Project. Acquired mutation of the tyrosine kinase JAK2 in human myeloproliferative disorders. Lancet 2005;365(9464):1054-61.
  10. Vainchenker W., Delhommeau F., Constantinescu S.N., Ber -nard O.A. New mutations and pathogenesis of myeloproliferative neoplasms. Blood 2011;118(7):1723-35.
  11. Konopleva M., Milella M., Ruvolo P., Watts J.C., Ricciardi M.R., Korchin B., McQueen T., Bornmann W., Tsao T., Bergamo P., Mak D.H., Chen W., McCubrey J., Tafuri A., Andreeff M. MEK inhibition enhances ABT-737-induced leukemia cell apoptosis via prevention of ERK-activated MCL-1 induction and modulation of MCL-1/BIM complex. Leukemia 2012;26(4):778-87.
  12. Benito J., Shi Y., Szymanska B., Carol H., Boehm I., Lu H., Konoplev S., Fang W., Zweidler-McKay P.A., Campana D., Borthakur G., Bueso-Ramos C., Shpall E., Thomas D.A., Jordan C.T., Kantarjian H., Wilson W.R., Lock R., Andreeff M., Konopleva M. Pronounced hypoxia in models of murine and human leukemia: high efficacy of hypoxia-activated prodrug PR-104. PLoS One 2011;6(8):e23108.
  13. Park H., Park S.G., Lee J.W., Kim T., Kim G., Ko Y.G., Kim S. Monocyte cell adhesion induced by a human aminoacyl-tRNA synthetase-associated factor, p43: identification of the related adhesion molecules and signal pathways. J Leukoc Biol 2002;71(2):223-30.
  14. Голенков А.К., Митина Т.А., Новиков В.В., Тагиров О.Т., Королева В.В., Крыжанов М.А., Луцкая Т.Д., Новиков Д.В., Барышников А.Ю. Клиническое значение растворимых молекул адгезии (sCD50-ICAM-3), апоптоза (SCD95) и sHLA класса I при лимфопролиферативных заболеваниях. Российский биотерапевтический журнал 2002;(1):60-4. [Golenkov A.K., Mitina T.A., Novikov V.V., Tagirov O.T., Koroleva V.V., Kryzhanov M.A., Lutskaya T.D., Novikov D.V., Baryshnikov A.Yu. Clinical significance of soluble adhesion molecules (sCD50-ICAM-3), apoptosis (SCD95) and sHLA class I in lymphoproliferative diseases. Rossiyskiy bioterapevticheskiy zhurnal 2002;(1):60-4 (in Russian)].
  15. Митина Т.А. Значение экспрессии дифференцировочных антигенов, молекул адгезии и FAS/APO в оценке клинического течения множественной миеломы и хронического лимфолейкоза. Российский биотерапевтический журнал 2002; (1):47-60. [Mitina T.A. Significance of expression of differentiation antigens, adhesion molecules, and AS/APO in assessment of clinical course of multiple myeloma and chronic lymphatic leukemia. Rossiyskiy bioterapevticheskiy zhurnal 2002;(1):47-60 (in Russian)].
  16. Sugiyama H., Inoue K., Ogawa H., Yamagami T., Soma T., Miyake S., Hirata M., Kishimoto T. The expression of IL-6 and its related genes in acute leukemia. Leuk Lymphoma 1996;21(1-2):49-52.
  17. Takahashi S., Harigae H., Ishii K.K., Inomata M., Fujiwara T., Yokoyama H., Ishizawa K., Kameoka J., Licht J.D., Sasaki T., Kaku M. Over-expression of Flt3 induces NF-kappaB pathway and increases the expression of IL-6. Leuk Res 2005; 29(8):893-9.
  18. Konopleva M., Konoplev S., Hu W., Zaritskey A.Y., Afanasiev B.V., Andreeff M. Stromal cells prevent apoptosis of AML cells by up-regulation of anti-apoptotic proteins. Leukemia 2002; 16(9):1713-24.

Copyright (c) 2016 Zakharov S.G., Golenkov A.K., Mitina T.A., Lutskaya T.D., Belousov K.A., Fadeev R.S., Solovieva M.E., Senotov A.S., Akatov V.S.

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