Skip to main content
PMC home page
British Journal of Cancer logoLink to British Journal of Cancer
. 2001 Dec;85(12):1987–1997. doi: 10.1054/bjoc.2001.2165

Mechanism of sensitization of MDR cancer cells by Pluronic block copolymers: Selective energy depletion

E V Batrakova 1, S Li 1, W F Elmquist 1, D W Miller 1, V Y Alakhov 2, A V Kabanov 1
PMCID: PMC2364003  PMID: 11747344

Abstract

This paper, for the first time, demonstrates that exposure of cells to the poly(ethylene oxide)-poly(propylene oxide) block copolymer, Pluronic P85, results in a substantial decrease in ATP levels selectively in MDR cells. Cells expressing high levels of functional P-glycoprotein (MCF-7/ADR, KBv; LLC-MDR1; Caco-2, bovine brain microvessel endothelial cells [BBMECs]) are highly responsive to Pluronic treatment, while cells with low levels of P-glycoprotein expression (MCF-7, KB, LLC-PK1, human umbilical vein endothelial cells [HUVECs] C2C12 myoblasts) are much less responsive to such treatment. Cytotoxicity studies suggest that Pluronic acts as a chemosensitizer and potentiates cytotoxic effects of doxorubicin in MDR cells. The ability of Pluronic to inhibit P-glycoprotein and sensitize MDR cells appears to be a result of ATP depletion. Because many mechanisms of drug resistance are energy dependent, a successful strategy for treating MDR cancer could be based on selective energy depletion in MDR cells. Therefore, the finding of the energy-depleting effects of Pluronic P85, in combination with its sensitization effects is of considerable theoretical and practical significance. © 2001 Cancer Research Campaign http://www.bjcancer.com

Keywords: ATP, doxorubicin, MDR, Pluronic, sensitisation

Full Text

The Full Text of this article is available as a PDF (128.0 KB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Alakhov VYu, Moskaleva EYu, Batrakova E. V., Kabanov A. V. Hypersensitization of multidrug resistant human ovarian carcinoma cells by pluronic P85 block copolymer. Bioconjug Chem. 1996 Mar-Apr;7(2):209–216. doi: 10.1021/bc950093n. [DOI] [PubMed] [Google Scholar]
  2. Altan N., Chen Y., Schindler M., Simon S. M. Defective acidification in human breast tumor cells and implications for chemotherapy. J Exp Med. 1998 May 18;187(10):1583–1598. doi: 10.1084/jem.187.10.1583. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Batrakova E. V., Dorodnych T. Y., Klinskii E. Y., Kliushnenkova E. N., Shemchukova O. B., Goncharova O. N., Arjakov S. A., Alakhov V. Y., Kabanov A. V. Anthracycline antibiotics non-covalently incorporated into the block copolymer micelles: in vivo evaluation of anti-cancer activity. Br J Cancer. 1996 Nov;74(10):1545–1552. doi: 10.1038/bjc.1996.587. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Batrakova E. V., Han H. Y., Miller D. W., Kabanov A. V. Effects of pluronic P85 unimers and micelles on drug permeability in polarized BBMEC and Caco-2 cells. Pharm Res. 1998 Oct;15(10):1525–1532. doi: 10.1023/a:1011942814300. [DOI] [PubMed] [Google Scholar]
  5. Batrakova E. V., Miller D. W., Li S., Alakhov V. Y., Kabanov A. V., Elmquist W. F. Pluronic P85 enhances the delivery of digoxin to the brain: in vitro and in vivo studies. J Pharmacol Exp Ther. 2001 Feb;296(2):551–557. [PubMed] [Google Scholar]
  6. Benderra Z., Morjani H., Trussardi A., Manfait M. Role of the vacuolar H+-ATPase in daunorubicin distribution in etoposide-resistant MCF7 cells overexpressing the multidrug-resistance associated protein. Int J Oncol. 1998 Mar;12(3):711–715. doi: 10.3892/ijo.12.3.711. [DOI] [PubMed] [Google Scholar]
  7. Drueckes P., Schinzel R., Palm D. Photometric microtiter assay of inorganic phosphate in the presence of acid-labile organic phosphates. Anal Biochem. 1995 Sep 1;230(1):173–177. doi: 10.1006/abio.1995.1453. [DOI] [PubMed] [Google Scholar]
  8. Evers R., Kool M., Smith A. J., van Deemter L., de Haas M., Borst P. Inhibitory effect of the reversal agents V-104, GF120918 and Pluronic L61 on MDR1 Pgp-, MRP1- and MRP2-mediated transport. Br J Cancer. 2000 Aug;83(3):366–374. doi: 10.1054/bjoc.2000.1260. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Evers R., Kool M., van Deemter L., Janssen H., Calafat J., Oomen L. C., Paulusma C. C., Oude Elferink R. P., Baas F., Schinkel A. H. Drug export activity of the human canalicular multispecific organic anion transporter in polarized kidney MDCK cells expressing cMOAT (MRP2) cDNA. J Clin Invest. 1998 Apr 1;101(7):1310–1319. doi: 10.1172/JCI119886. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Evers R., Zaman G. J., van Deemter L., Jansen H., Calafat J., Oomen L. C., Oude Elferink R. P., Borst P., Schinkel A. H. Basolateral localization and export activity of the human multidrug resistance-associated protein in polarized pig kidney cells. J Clin Invest. 1996 Mar 1;97(5):1211–1218. doi: 10.1172/JCI118535. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Ferrari M., Fornasiero M. C., Isetta A. M. MTT colorimetric assay for testing macrophage cytotoxic activity in vitro. J Immunol Methods. 1990 Aug 7;131(2):165–172. doi: 10.1016/0022-1759(90)90187-z. [DOI] [PubMed] [Google Scholar]
  12. Fontaine M., Elmquist W. F., Miller D. W. Use of rhodamine 123 to examine the functional activity of P-glycoprotein in primary cultured brain microvessel endothelial cell monolayers. Life Sci. 1996;59(18):1521–1531. doi: 10.1016/0024-3205(96)00483-3. [DOI] [PubMed] [Google Scholar]
  13. Garewal H. S., Ahmann F. R., Schifman R. B., Celniker A. ATP assay: ability to distinguish cytostatic from cytocidal anticancer drug effects. J Natl Cancer Inst. 1986 Nov;77(5):1039–1045. [PubMed] [Google Scholar]
  14. Goldstein L. J., Pastan I., Gottesman M. M. Multidrug resistance in human cancer. Crit Rev Oncol Hematol. 1992;12(3):243–253. doi: 10.1016/1040-8428(92)90057-w. [DOI] [PubMed] [Google Scholar]
  15. Hayes J. D., Pulford D. J. The glutathione S-transferase supergene family: regulation of GST and the contribution of the isoenzymes to cancer chemoprotection and drug resistance. Crit Rev Biochem Mol Biol. 1995;30(6):445–600. doi: 10.3109/10409239509083491. [DOI] [PubMed] [Google Scholar]
  16. Iwahana M., Utoguchi N., Mayumi T., Goryo M., Okada K. Drug resistance and P-glycoprotein expression in endothelial cells of newly formed capillaries induced by tumors. Anticancer Res. 1998 Jul-Aug;18(4C):2977–2980. [PubMed] [Google Scholar]
  17. Kaplan O., Jaroszewski J. W., Clarke R., Fairchild C. R., Schoenlein P., Goldenberg S., Gottesman M. M., Cohen J. S. The multidrug resistance phenotype: 31P nuclear magnetic resonance characterization and 2-deoxyglucose toxicity. Cancer Res. 1991 Mar 15;51(6):1638–1644. [PubMed] [Google Scholar]
  18. Kaplan O., Navon G., Lyon R. C., Faustino P. J., Straka E. J., Cohen J. S. Effects of 2-deoxyglucose on drug-sensitive and drug-resistant human breast cancer cells: toxicity and magnetic resonance spectroscopy studies of metabolism. Cancer Res. 1990 Feb 1;50(3):544–551. [PubMed] [Google Scholar]
  19. Kirillova G. P., Mokhova E. N., Dedukhova V. I., Tarakanova A. N., Ivanova V. P., Efremova N. V., Topchieva I. N. The influence of pluronics and their conjugates with proteins on the rate of oxygen consumption by liver mitochondria and thymus lymphocytes. Biotechnol Appl Biochem. 1993 Dec;18(Pt 3):329–339. [PubMed] [Google Scholar]
  20. Lee J. S., Paull K., Alvarez M., Hose C., Monks A., Grever M., Fojo A. T., Bates S. E. Rhodamine efflux patterns predict P-glycoprotein substrates in the National Cancer Institute drug screen. Mol Pharmacol. 1994 Oct;46(4):627–638. [PubMed] [Google Scholar]
  21. Mansouri A., Henle K. J., Nagle W. A. Multidrug resistance: prospects for clinical management. SAAS Bull Biochem Biotechnol. 1992 Jan;5:48–52. [PubMed] [Google Scholar]
  22. Miller D. W., Fontain M., Kolar C., Lawson T. The expression of multidrug resistance-associated protein (MRP) in pancreatic adenocarcinoma cell lines. Cancer Lett. 1996 Oct 22;107(2):301–306. doi: 10.1016/0304-3835(96)04384-4. [DOI] [PubMed] [Google Scholar]
  23. Rebbeor J. F., Senior A. E. Effects of cardiovascular drugs on ATPase activity of P-glycoprotein in plasma membranes and in purified reconstituted form. Biochim Biophys Acta. 1998 Feb 2;1369(1):85–93. doi: 10.1016/s0005-2736(97)00185-5. [DOI] [PubMed] [Google Scholar]
  24. Shepard R. L., Winter M. A., Hsaio S. C., Pearce H. L., Beck W. T., Dantzig A. H. Effect of modulators on the ATPase activity and vanadate nucleotide trapping of human P-glycoprotein. Biochem Pharmacol. 1998 Sep 15;56(6):719–727. doi: 10.1016/s0006-2952(98)00212-3. [DOI] [PubMed] [Google Scholar]
  25. Venne A., Li S., Mandeville R., Kabanov A., Alakhov V. Hypersensitizing effect of pluronic L61 on cytotoxic activity, transport, and subcellular distribution of doxorubicin in multiple drug-resistant cells. Cancer Res. 1996 Aug 15;56(16):3626–3629. [PubMed] [Google Scholar]
  26. Zaman G. J., Lankelma J., van Tellingen O., Beijnen J., Dekker H., Paulusma C., Oude Elferink R. P., Baas F., Borst P. Role of glutathione in the export of compounds from cells by the multidrug-resistance-associated protein. Proc Natl Acad Sci U S A. 1995 Aug 15;92(17):7690–7694. doi: 10.1073/pnas.92.17.7690. [DOI] [PMC free article] [PubMed] [Google Scholar]

Articles from British Journal of Cancer are provided here courtesy of Cancer Research UK

RESOURCES