Advertisement

Alteration of red blood cell microrheology by anti-tumor chemotherapy drugs

  • I. A. Tikhomirova
  • A. V. Muravyov
  • E. P. Petrochenko
  • N. V. Kislov
  • S. V. Cheporov
  • E. V. Peganova
Articles

Abstract

The aim of this study was to estimate effects of some chemotherapy drugs on the elasticity and deformability of the membrane of a red blood cell (RBC). It was found that incubation of red blood cells (RBCs) with cisplatin or epoetin alpha led to considerable (by 10–17%; p < 0.05) increase in the RBC deformability and that cisplatin could activate tyrosine protein kinases (TPKs). Preincubation of RBCs with a specific inhibitor of EGF-R and Src kinase, lavendustin A, almost completely prevented the cisplatin effect. Tyrosine phosphatase inhibitor, sodium orthovanadate, increased the RBC deformability (p < 0.05). This effect was also abandoned by lavendustin A. To test a hypothesis on the involvement of protein kinases of mature RBCs in control of their membrane elasticity, the cells were incubated with phorbol 12-myristate 13-acetate (PMA) activating protein kinase Cα (PKCα). PMA increased the RBC deformability only moderately (by 8%, p < 0.05) and the effect was canceled by nonselective and selective PKC inhibitors staurosporin and 4-(1-methylindol-3-yl)maleimide hydrochloride. Erythropoietin is known to inhibit the nonselective cation channels of the RBC membrane; however, preincubation of the cells with verapamil did not cancel the increase in their deformability. Hence, this increase in deformability could be a result of the action of tyrosine protein kinases, the more so that this effect was almost completely canceled by lavendustion A. The results suggest that the presence of functionally active protein kinases and phosphatases in the membranes of mature RBC makes them a target for the addressed effects of signal molecules, including some chemotherapy drugs, causing consecutive alterations in the RBC membrane elasticity, microrheological properties, and transport potential.

Keywords

erythrocyte membrane deformability signaling pathways cisplatin doxorubicin epoetin alpha 5-fluorouracil 

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 1.
    Caro C.G., Pedley T.J., Schroter R.C., Seed W.A. 1981. The mechanics of the circulation. M.: Mir.Google Scholar
  2. 2.
    Baskurt O.K., Meiselman H.J. 2003. Blood rheology and hemodynamics. Semin. Thromb. Hemost. 29, 435–450.CrossRefPubMedGoogle Scholar
  3. 3.
    Priers A.R., Secomb T. 2003. Rheology of the microcirculation. Clin. Hemorheol. Microcirc. 29, 143–148.Google Scholar
  4. 4.
    Reglin B., Secomb T.W., Pries A.R. 2009. Structural adaptation of microvessel diameters in response to metabolic stimuli: where are the oxygen sensors? Amer. J. Physiol. Heart. 297, H2206–H2219.CrossRefGoogle Scholar
  5. 5.
    Oonishi T., Sakashita K., Uysaka N. 1997. Regulation of red blood cell filterability by Ca2+ influx and cAMPmediated signaling pathways. Am. J. Physiol. 273, 1828–1834.Google Scholar
  6. 6.
    Muravyov A.V., Yakusevich V.V., Maimistova A.A., Chuchkanov F.A., Bulaeva S.V. 2007. Hemorheological efficiency of drugs, targeting on intracellular phosphodiesterase activity: In vitro study. Clin. Hemorheol. Microcirc. 24, 19–23.Google Scholar
  7. 7.
    De Oliveira S., Silva-Herdade A., Saldanha C. 2008. Modulation of erythrocyte deformability by PKC activity. Clin. Hemorheol. Microcirc. 39, 363–373.PubMedGoogle Scholar
  8. 8.
    Muravyov A.V., Tikhomirova I.A. 2013. Role molecular signaling pathways in changes of red blood cell deformability. Clin. Hemorheol. Microcirc. 53 (1–2), 45–59.PubMedGoogle Scholar
  9. 9.
    Minetti G., Ciana A., Balduini C. 2004. Differential sorting of tyrosine kinases and phosphotyrosine phosphatases acting on band 3 during vesiculation of human erythrocytes. Biochem. J. 377, 489–497.CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Sundquist J., Bias S., Hogan J., Faith B., Davis P. 1999. The a1-adrenergic receptor in human erythrocyte membranes mediates interaction in vitro of epinephrine and thyroid hormone at the membrane Ca2+-ATPase. Cellular Signalling. 24, 795–799.Google Scholar
  11. 11.
    Romero P.J., Romero E.A. 2003. New vanadateinduced Ca2+ pathway in human red cells. Cell Biol. Int. 27, 903–912.CrossRefPubMedGoogle Scholar
  12. 12.
    Nunomura W., Takakuwa Y. 2006. Regulation of protein 4.1R interactions with membrane proteins by Ca2+ and calmodulin. Front. Biosci. 11, 1522–1539.CrossRefPubMedGoogle Scholar
  13. 13.
    Muravyov A.V., Tikhomirova I.A. 2015. Red blood cell microrheological changes and drug transport efficiency. J. Cell. Biotechnol. 1, 45–51.CrossRefGoogle Scholar
  14. 14.
    Dintenfass L. 1977. Theoretical aspects and clinical applications of the blood viscosity equation containing a term for the internal viscosity of the red cell. Blood Cells. 3, 367–374.Google Scholar
  15. 15.
    Muravyov A.V., Mikhaylova S.G., Tikhomirova I.A. 2014. Role of the intracellular signaling systems in regulation of erythrocyte microrheology. Biol. membrany (Rus.). 31, 1–7.Google Scholar
  16. 16.
    Andrews D.A., Yang Lu., Low Ph.S. 2002. Phorbol ester stimulates a protein kinase C-mediated agatoxin-TK-sensitive calcium permeability pathway in human red blood cells. Blood. 100, 3392–3399.CrossRefPubMedGoogle Scholar
  17. 17.
    Manno S., Takakuwa Y., Mohandas N. 2005. Modulation of erythrocyte membrane mechanical function by protein 4.1 phosphorylation. J. Biol. Chem. 280, 7581–7587.CrossRefPubMedGoogle Scholar
  18. 18.
    Bragadin M., Ion-Popa F., Clari G., Bordin L. 2007. SHP-1 tyrosine phosphatase in human erythrocytes. Ann. N.Y. Acad. Sci. 1095, 193–203.CrossRefPubMedGoogle Scholar
  19. 19.
    Mohandas N., Gallagher P.G. 2008. Red cell membrane: Past, present, and future. Blood. 12, 3939–3948.CrossRefGoogle Scholar
  20. 20.
    Mallozzi C., Di Stasi A.M., Minetti M. 1997. Peroxynitrite modulates tyrosine-dependent signal transduction pathway of human erythrocyte band 3. FASEB. 11, 1281–1290.Google Scholar
  21. 21.
    Govekar R.B., Zingde S.M. 2001. Protein kinase C isoforms in human erythrocytes Ann. Hematol. 80, 531–534.Google Scholar
  22. 22.
    De Franceschi L., Fumagalli L., Olivieri O., Corrocher R., Lowell C.A., Berton G. 1997. Deficiency of Src family kinases Fgr and Hck results in activation of erythrocyte K/Cl cotransport. J. Clin. Invest. 99 (2), 220–227.CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Ingley E. 2012. Functions of the Lyn tyrosine kinase in health and disease. Cell Commun. Signal. 10 (1), 21–32.CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Luttrell D.K., Luttrell L.M. 2004. Not so strange bed fellows: G-protein-coupled receptors and Src family kinases. Oncogene. 23 (48), 7969–7978.CrossRefPubMedGoogle Scholar
  25. 25.
    Zipser Y., Kosower N.S. 1996. Phosphotyrosine phosphatase associated with band 3 protein in the human erythrocyte membrane. Biochem. J. 314, 881–887.CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Pantaleo A., Ferru E., Giribaldi G., Mannu F., Carta F., Matte A., de Franceschi L., Turrini F. 2009. Oxidized and poorly glycosylated band 3 is selectively phosphorylated by Syk kinase to form large membrane clusters in normal and G6PD-deficient red blood cells. Biochem. J. 418 (2), 359–367.CrossRefPubMedGoogle Scholar
  27. 27.
    Hu D.E., Fan T.P. 1995. Suppression of VEGFinduced angiogenesis by the protein tyrosine kinase inhibitor, lavendustin A. Br. J. Pharmacol. 114, 262–268.CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Kumar R., Shrivastava A., Sodhi A. 1995. Cisplatin stimulates protein tyrosine phosphorylation in macrophages. Biochem. Mol. Biol. Int. 35, 541–547.PubMedGoogle Scholar
  29. 29.
    Singh R.A., Sodhi A. 1998. Expression and activation of lyn in macrophages treated in vitro with cisplatin: Regulation by kinases, phosphatases and Ca2+/calmodulin. Biochim. Biophys. Acta. 1405, 171–179.CrossRefPubMedGoogle Scholar
  30. 30.
    Zipser Y., Piade A., Barbul A., Korenstein R., Kosower N.S. 2002. Ca2+ promotes erythrocyte band 3 tyrosine phosphorylation via dissociation of phosphotyrosine phosphatase from band 3. Biochem. J. 368 (Pt 1), 137–144.CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Ling E., Danilov Y.N., Cohen C.M. 1988. Modulation of red cell band 4.1 function by cAMP-dependent kinase and protein kinase C phosphorylation. J. Biol. Chem. 263, 2209–2216.PubMedGoogle Scholar
  32. 32.
    Silva-Herdade A.S., Freitas T., Almeida J.P., Saldanha C. 2015. Erythrocyte deformability and nitric oxide mobilization under pannexin-1 and PKC dependence. Clin. Hemorheol. Microcirc. 59 (2), 155–162.PubMedGoogle Scholar
  33. 33.
    Salomao M., Zhang X., Yang Y., Lee S., Hartwig J.H., Chasis J.A., Mohandas N., An X. 2008. Protein 4.1Rdependent multiprotein complex: New insights into the structural organization of the red blood cell membrane. Proc. Natl. Acad. Sci. USA. 105, 8026–8031.CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Baciu I., Ivanof L., Pavel T. 1985. Erythropoietin binding to the red cell membranes. Physiologie. 22, 227–231.PubMedGoogle Scholar
  35. 35.
    Yoshimura A., Arai K. 1996. Physician education: The erythropoietin receptor and signal transduction. Oncologist. 1, 337–339.PubMedGoogle Scholar
  36. 36.
    De Franceschi L., Fumagalli L., Olivieri O., Corrocher R., Lowell C.A., Berton G. 1997. Deficiency of Src family kinases Fgr and Hck results in activation of erythrocyte K/Cl cotransport. J. Clin. Invest. 99 (2), 220–227.CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    Avdonin P.V., Tkachuk V.A. 1994. Retseptory i vnutrikletochnyi kaltsii (Receptors and intracellular calcium). M.: Nauka.Google Scholar
  38. 38.
    Tong W., Zhang J., Lodish H.F. 2005. Lnk inhibits erythropoiesis and Epo-dependent JAK2 activation and downstream signaling pathways. Blood. 15, 4604–4612.CrossRefGoogle Scholar
  39. 39.
    Ruetten H., Thiemermann C. 1997. Effects of tyrphostins and genistein on the circulatory failure and organ dysfunction caused by endotoxin in the rat: A possible role for protein tyrosine kinase. Br. J. Pharmacol. 122 (1), 59–70.CrossRefPubMedPubMedCentralGoogle Scholar
  40. 40.
    Chin H., Arai A., Wakao H., Kamiyama R., Miyasaka N., Miura O. 1998. Lyn physically associates with the erythropoietin receptor and may play a role in activation of the Stat5 pathway. Blood. 91 (10), 3734–3745.PubMedGoogle Scholar

Copyright information

© Pleiades Publishing, Ltd. 2016

Authors and Affiliations

  • I. A. Tikhomirova
    • 1
  • A. V. Muravyov
    • 1
  • E. P. Petrochenko
    • 1
  • N. V. Kislov
    • 1
  • S. V. Cheporov
    • 1
  • E. V. Peganova
    • 1
  1. 1.Ushinky Yaroslavl State Pedagogical UniversityYaroslavlRussia

Personalised recommendations