Skip to main content
SpringerLink
Log in

Multidrug resistance p-glycoprotein inhibits antiapoptotic action of mitochondria-targeted antioxidant SkQR1

  • Published:
Cell and Tissue Biology Aims and scope Submit manuscript

Abstract

Mitochondria-targeted antioxidants of the SkQ family that accumulate in energized mitochondria protect cells from oxidative stress by increasing the level of reduced glutathione and decreasing cell damage induced by hydrogen peroxide. The exposure of various human transformed cell lines to SkQR1, a fluorescent member of the SkQ family, showed that SkQR1 was pumped out of the chemotherapy resistant cells by P-glycoprotein, one of the main transport proteins that determines multidrug resistance typical for many neoplastic cells. It was also shown that SkQR1 pumping is neutralized by P-glycoprotein inhibitors (verapamil and pluronic L61). In experiments on K-562 cells, it was found that the subline sensitive to chemotherapy is protected by SkQR1 from apoptosis induced by hydrogen peroxide. The protection of resistant subline cells is only evident after the inhibition of P-glycoprotein.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  • Ambudukar, S.V., Dey, S., Hrycina, C.A., Ramachandra, M., and Gottesman, M.M., Biochemical, Cellular and Pharmacological Aspects of the Multidrug Transporter, Ann. Rev. Pharmacol. Toxicol., 1999, vol. 39, pp. 361–398.

    Article  Google Scholar 

  • Antonenko, Yu.N., Avetisyan, A.V., and Bakeeva, L.E., Mitochondria-Targeted Plastoquinone Derivatives As Tools to Interrupt Execution of the Aging Program. 1. Cationic Plastoquinone Derivatives: Synthesis and in vitro Studies, Biokhimiya, 2008, vol. 73, no. 12, pp. 1589–1606 [Biochemistry (Mosc.), 2008, vol. 73, no. 12, pp. 1273–1287.].

    Google Scholar 

  • Bakeeva, L.E., Grinius, L.I., Jasaitis, A.A., Kuliene, V.V., Levitsky, D.O., Liberman, E.A., Severina, I.I., and Sculachev, V.P., Conversion of Biomembrane-Produced Energy into Electric Form. II. Intact Mitochondria. Biochim. Biophys. Acta, 1970, vol. 216, pp. 12–21.

    Google Scholar 

  • Carmichael, J., De Graff, W.G., Gazdar, A.F., Minna, D., and Mitchel, J.B., Evaluation of a Tetrazolium-Based Semiautomated Colorimetric Assay: Assessment of Chemosensitivity Testing, Cancer Res., 1987, vol. 47, pp. 936–942.

    PubMed  CAS  Google Scholar 

  • Demina, T., Grosdova, I., Krylova, O., Zhirnov, V., Frey, H., Kaluz, H., and Melik-Nubarov, N., Relationship between the Structure of Amphiphilic Copolymers and Their Ability to Disturb Lipid Bilayers. Biochemistry, 2005, vol. 44, pp. 4042–4054.

    Article  PubMed  CAS  Google Scholar 

  • Demina, T.V., Interaction of Amphiphilic Polymers with Natural and Model Membranes, Extended Abstract of Candidate’s (Biol.) Dissertation, Moscow, 2007.

  • Dreuw, A., Hermanns, H.M., Heise, R., Joussen, S., Rodrigues, F., Marquardt, Y., Jugert, F., Merk, H.F., Heinrich, P.C., and Baron, J.M., Interleukin-6-Type Cytokines Upregulate Expression of Multidrug Resistance-Associated Proteins in NHEK and Dermal Fibroblasts, J. Invest. Dermatol., 2005, vol. 124, pp. 28–37.

    Article  PubMed  CAS  Google Scholar 

  • Fetisova, E.K., Avetisyan, A.V., Izyumov, D.S., Korotetskaya, M.V., Chernyak, B.V., and Skulachev, V.P., Mitochondria-Targeted Antioxidant SkQR1 Selectively Protects MDR (Pgp170)-Negative Cells against Oxidative Stress, FEBS Letts., 2010, vol. 584, pp. 562–566.

    Article  CAS  Google Scholar 

  • Griffith, O.W., Glutathione and Glutathione Disulphide, in Methods of Enzymatic Analysis, 3rd ed., VCH-Verlagsgesellschaft, Weinheim, 1985, vol. 8, pp. 521–529.

    Google Scholar 

  • Higgins, C.F. and Gottesman, M.M., Is the Multidrug Transporter a Flipase? Trends Biochem. Sci., 1992, vol. 17, pp. 18–21.

    Article  PubMed  CAS  Google Scholar 

  • Kabanov, A.V., Batrakova, E.V., and Alakhov, V.V., Pluronic Block Copolymers for Overcoming Drug Resistance in Cancer. Adv. Drug Deliv. Rev., 2002, vol. 54, pp. 759–779.

    Article  PubMed  CAS  Google Scholar 

  • Kalininà, E.V., Chernov, N.N., Saprin, A.N. Kotova, Y.N., Andreev, Y.A., Solomka, V.S., and Schertbak, N.P., Changes in Expression of Genes Encoding Antioxidant Enzymes, Heme Oxigenase-1, Bcl-2, and Bcl-xl and Level of Reactive Oxygen Species in Tumor Cells Resistant to Doxorubicin, Biochemistry, 2006, vol. 71, pp. 1200–1206.

    PubMed  Google Scholar 

  • Kelso, G. F., Porteous, C.M., Hughes, G., Ledgerwood, E.C., Gane, A.M., Smith, R.A., and Murphy, M.P. Prevention of Mitochondrial Oxidative Damage using Targeted Antioxidants. Ann. N.Y. Acad. Sci., 2002, vol. 959, pp. 263–274.

    Article  PubMed  CAS  Google Scholar 

  • Lewis, K., Multidrug Resistance Pumps in Bacteria: Variations on a Theme, Trends Biochem. Sci., 1994, vol. 19, pp. 119–123.

    Article  PubMed  CAS  Google Scholar 

  • Liberman, E.A. and Skulachev, V.P., Conversion of Biomembrane-Produced Energy into Electric Form. IV. General Discussion, Biochim. Biophys. Acta, 1970, vol. 216, pp. 30–42.

    Article  PubMed  CAS  Google Scholar 

  • Liberman, E.A., Topali, V.P., Tsofina, L.M., Jasaitis, A.A., and Skulachev, V.P., Mechanism of Coupling of Oxidative Phosphorylation and the Membrane Potential of Mitochondria, Nature, 1969, vol. 222, pp. 1076–1078.

    Article  PubMed  CAS  Google Scholar 

  • Murphy, M.P. and Smith, R.A., Targeting Antioxidants to Mitochondria by Conjugation to Lipophilic Cations, Annu. Rev. Pharmacol. Toxicol., 2007, vol. 47, pp. 629–656.

    Article  PubMed  CAS  Google Scholar 

  • Neifakh, A. A., Multidrug Resistance: A Solution to the Problem, Biol. Membr., 2003, vol. 20, no. 3, pp. 206–212.

    Google Scholar 

  • Ng, W.W., Sarangi, F., Zastawny, R.L., Veinot-Drebot, L., and Ling, V., Identification of Members of the P-Glycoprotein, Multigene Family, Mol. Cell. Biol., 1989, vol. 9, pp. 1224–1232.

    PubMed  CAS  Google Scholar 

  • Pannecouque, C., Daelemans, D., and De Clercq, E., Tetrazolium-Based Colorimetric Assay for the Detection of HIV Replication Inhibitors: Revisited 20 Years Later, Nature Protocols, 2008, vol. 3, pp. 427–434.

    Article  PubMed  CAS  Google Scholar 

  • Safa, A.R., Photoaffinity Labeling of the Multidrug-Resistance-Related P-Glycoprotein with Photoactive Analogs of Verapamil, Proc. Natl. Acad. Sci. USA, 1988, vol. 85, pp. 7187–7191.

    Article  PubMed  CAS  Google Scholar 

  • Saretzki, G., Murphy, M.P., and von Zglinicki, T., MitoQ Counteracts Telomere Shortening and Elongates Lifespan of Fibroblasts Under Mild Oxidative Stress, Aging Cell, 2003, vol. 2, pp. 141–143.

    Article  PubMed  CAS  Google Scholar 

  • Schulz, J.B., Lindenau, J., Seyfried, J., and Dichgans, J., Glutathione, Oxidative Stress and Neureodegeneration, Eur. J. Biochem., 2000, vol. 267, pp. 4904–4911.

    Article  PubMed  CAS  Google Scholar 

  • Skulachev, V.P., A Biochemical Approach to the Problem of Aging: “Megaproject” on Membrane-Penetrating Ions. The First Results and Prospects, Biokhimiya, 2007, vol, 72, no. 12, pp. 1700–1714 [Biochemistry (Mosc.), 2007, vol, 72, no. 12, pp. 1385–1398].

    Google Scholar 

  • Stavrovskaya, A.A., Cellular Mechanisms of Multidrug Resistance of Tumor Cells, Biokhimiya, 2000, vol. 65, no. 1, pp. 112–126 [Biochemistry (Mosc.), 2000, vol. 65, no. 1, pp. 95–106].

    Google Scholar 

  • Tsuruo, T. and Yusa, K., Reversal Mechanism of Multidrug Resistance by Verapamil: Direct Binding of Verapamil to P-Glycoprotein on Specific Sites and Transport of Verapamil Outward Across the Plasma Membrane of K562/ADM Cells, Cancer Res., 1989, vol. 49, pp. 5002–5006.

    PubMed  Google Scholar 

  • Van der Bliek, A.M. and Borst, P., Multidrug Resistance, Adv. Cancer Res., 1989, vol. 52, pp. 165–198.

    Article  PubMed  Google Scholar 

  • Zhirnov, A.E., Pavlov, D.N., Demina, T.V., Badun, G.A., Grozdova, I.D., and Melik-Nubarov, N.S., Effect of the Structure of Ethylene Oxide-Propylene Oxide Block Copolymers on Their Interaction with Biological Membranes, Vysokomolek. Soed. Ser. A, 2006, vol. 48, no. 11, pp. 1–11 [Pol. Sci. Ser. A, 2006, vol. 48, no. 11, pp. 1202–1211].

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Belozerskii Institute of Physicochemical Biology of Moscow State University, Moscow, Russia

    E. K. Fetisova, A. V. Avetisyan, D. S. Izyumov, M. V. Korotetskaya, V. N. Tashlitskii, V. P. Skulachev & B. V. Chernyak

Authors
  1. E. K. Fetisova
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. A. V. Avetisyan
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. D. S. Izyumov
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. M. V. Korotetskaya
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. V. N. Tashlitskii
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. V. P. Skulachev
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. B. V. Chernyak
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to E. K. Fetisova.

Additional information

Original Russian Text © E.K. Fetisova, A.V. Avetisyan, D.S. Izyumov, M.V. Korotetskaya, V.N. Tashlitskii, V.P. Skulachev, B.V. Chernyak, 2010, published in Tsitologiya, Vol. 52, No. 12, 2010, pp. 1031–1041.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Fetisova, E.K., Avetisyan, A.V., Izyumov, D.S. et al. Multidrug resistance p-glycoprotein inhibits antiapoptotic action of mitochondria-targeted antioxidant SkQR1. Cell Tiss. Biol. 5, 37–46 (2011). https://doi.org/10.1134/S1990519X11010056

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1134/S1990519X11010056

Keywords

Search

Navigation