Multidrug Resistance Reversal on Cancer Cells by Selected Carotenoids, Flavonoids and Anthocyanins

  • Joseph Molnár
  • Helga Engi
  • Nóra Gyémánt
  • Zsuzsanne Schelz
  • Gabriella Spengler
  • Imre Ocsovski
  • Miklós Szücs
  • Judith Hohmann
  • Margaret Szabo
  • Lajos Tanács
  • Péter Molnár
  • Joseph Deli
  • Liselotte Krenn
  • Masami Kawase
  • Hidetsugu Wakabayashi
  • Teruo Kurihara
  • Yoshiaki Shirataki
  • Hiroshi Sakagami
  • Noboru Motohashi
  • Remigijus Didiziapetris
Part of the Topics in Heterocyclic Chemistry book series (TOPICS, volume 15)


The multidrug resistance (MDR) proteins which belong to the ATP-binding cassette superfamily are present in a majority of human tumors and are an important final cause of therapeutic failure. Therefore, some compounds which inhibit the function of the MDR-efflux proteins may improve the cytotoxic action in cancer chemotherapy. The mechanism of action was believed to be a competition between their resistance modifiers and the cytotoxic agents for the same binding site of MDR P-glycoprotein (P-gp) due to a complementarity with a hypothetic receptor site with unknown structure. In the absence of the crystal structures of the P-gp, a receptor fitting was not available. Therefore, we tried to indirectly define the receptor structure or mapping of human MDR1-encoded P-gp in the presence of the structurally unrelated carotenoids, flavonoids, isoflavones and terpenoids.

The inhibition of the efflux activity was measured by the increase of rhodamine 123 (R123) uptake by cancer cells. The effects of flavonoids, carotenoids and anthocyanins were studied on the activity of the MDR-1 gene-encoded efflux pump system. The effective flavonoids were rotenone, chrysin, phloretin and sakuranetin, which could inhibit the MDR efflux pump in the mouse lymphoma and colon cancer cells. The carotenoids isolated from paprika and other vegetables were tested on the increase of R123 accumulation of human MDR-1 gene-transfected L1210 mouse lymphoma cells and human breast cancer cells MDA-MB-231 (HTB-26). Capsanthin and capsorubin enhanced the R123 accumulation 30-fold relative to the nontreated lymphoma cells. Lycopene, lutein, antheraxanthin and violaxanthin had moderate effects, whereas α- and β-carotene had no effect on the reversal of MDR in the cancer cells. The MDR reversal of anthocyanins such as callistephin chloride, pelargonin chloride, ideaninchloride and pelargonidin chloride were studied. Cyanin chloride slightly increased the activity of P-gp; however, all other flavonoids were ineffective as resistance modifiers. Their biological ineffectivity is possibly related to the differences on the polarities of their compounds and permanent positive charge.

Anthocyanins Flavonoids Carotenoids Isoflavones Multidrug resistance reversal  


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  1. 1.
    Szent-Györgyi A (1933) Nature 131:225 CrossRefGoogle Scholar
  2. 2.
    Szent-Györgyi A (1933) Nature 131:24 CrossRefGoogle Scholar
  3. 3.
    Banga I, Szent-Györgyi A (1934) Biochem J 28:1625 Google Scholar
  4. 4.
    Szent-Györgyi A, Foreword MR (1936) Paprika from foodtechnical and dietetical point of view. Leipzig, Barth [III]. Nature, p 1939 Google Scholar
  5. 5.
    Szent-Györgyi A (1939) US Patent 2152827 Google Scholar
  6. 6.
    Molnár J, Szabó D, Pusztai R, Mucsi I, Berek L, Ocsovszki I, Kawata E, Shoyama Y (2000) Anticancer Res 20:861 Google Scholar
  7. 7.
    Bollag W (1994) Pure Appl Chem 66:995 CrossRefGoogle Scholar
  8. 8.
    Nishino H, Tokuda H, Satomi Y, Masuda M, Bu P, Onozuka M, Ymaguchi S, Ichiishi E, Murakoshi M, Kato T, Misawa N, Narisawa T, Takasuka N, Yano M (1999) Pure Appl Chem 71:2273 CrossRefGoogle Scholar
  9. 9.
    Mayne ST (1999) In: Abstracts of the 12th international carotenoid symposium, Cairns, Australia, 18–23 July 1999 Google Scholar
  10. 10.
    Manoharan K, Som S, Chatterjee M, Banerjee MR (1984) Carcinogenesis 5:937 CrossRefGoogle Scholar
  11. 11.
    Murakoshi M, Nishino H (1992) Cancer Res 52:6583 Google Scholar
  12. 12.
    Smaller B, Isenberg I, Baird SL (1961) Nature 191:168 CrossRefGoogle Scholar
  13. 13.
    Motohasi N, Kurihara T, Wakabayashi H, Yaji M, Mucsi I, Molnár J, Maruyama S, Sakagami H, Nakasima H, Tani S, Shirataki Y, Kawase M (2001) In Vivo 15:437 Google Scholar
  14. 14.
    Gyémánt N, Tanaka M, Molnár P, Deli J, Mándoky L, Molnár J (2006) Anticancer Res 26:367 Google Scholar
  15. 15.
    Eley DD, Snart RS (1965) Biochim Biophys Acta 102:379 CrossRefGoogle Scholar
  16. 16.
    Molnár J, Gyémánt N, Tanaka M, Hohmann J, Bergrmann-Leitner E, Molnár P, Deli J, Didiziapetris R, Ferreira MJU (2006) Curr Pharm Design 12:287 CrossRefGoogle Scholar
  17. 17.
    Cornwell MM, Pastan I, Gottesmann MM (1987) J Biol Chem 262:2166 Google Scholar
  18. 18.
    Deli J, Molnár P, Tóth G, Baumeler A, Eugster CH (1991) Helv Chim Acta 74:819 CrossRefGoogle Scholar
  19. 19.
    Huggins CM, Le Blanc OH (1960) Nature 186:552 CrossRefGoogle Scholar
  20. 20.
    Motohashi N, Wakabayashi H, Kurihara T, Takada Y, Maruyama S, Sakagami H, Nakashima H, Tani S, Shiratakim Y, Kawase M, Wolfard K, Molnár J (2003) Phytotherapy Res 17:348 CrossRefGoogle Scholar
  21. 21.
    Deli J, Molnár P, Matus Z, Traber B, Pfander H (2001) Tetrahedron Lett 42:1395 CrossRefGoogle Scholar
  22. 22.
    Khachik F, Nir Z, Ausich RL (1997) In: Ohigashi H (ed) Proceedings of the 2nd international conference on food factors: chemistry and cancer prevention. Springer, Tokyo, p 204 Google Scholar
  23. 23.
    Deli J, Molnár P, Õsz E, Tóth G (2000) Tetrahedron Lett 41:8153 CrossRefGoogle Scholar
  24. 24.
    Mele A, Mendichi R, Selva A, Molnár P, Tóth G (2002) Carbohydrate Res 337:1129 CrossRefGoogle Scholar
  25. 25.
    Van Breemen RB, Xu X, Wang Y, Constantinou A, Bowen PE (1999) In: Abstracts of the 12th international carotenoid symposium, Cairns, Australia, 18–23 July 1999 Google Scholar
  26. 26.
    Nahum A, Amir H, Danilenko M, Karas M, Giat Y, Levy J, Sharoni Y (1999) In: Abstracts of the 12th international carotenoid symposium, Cairns, Australia, 18–23 July 1999 Google Scholar
  27. 27.
    Sharoni Y, Karas M, Amir H, Giat J, Danilenko M, Levy J (1996) In: Abstracts of the 11th International Symposium on Carotenoids, Leiden, The Netherlands, August 18–23 1996 Google Scholar
  28. 28.
    Kleinman D, Karas M, Roberts CT Jr, LeRoith D, Phillip M, Segev Y, Levy J, Sharoni Y (1995) Endocrinol 136:2531 CrossRefGoogle Scholar
  29. 29.
    Nishino H (1999) In: Abstracts of the 12th international carotenoid symposium, Cairns, Australia, 18–23 July 1999 Google Scholar
  30. 30.
    Simoni D, Roberti M, Invidiata FP, Rondanin R, Baruchello R, Malagutti C, Mazzali A, Rossi M, Grimaudo S, Capone F, Dusonchet L, Meli M, Raimond MV, Landino M, D'Alessandro N, Tolomeo M, Arindam D, Lu S, Benbrook DM (2001) J Med Chem 2308 Google Scholar
  31. 31.
    Lowe GM, Booth LA, Young AJ, Bilton RF (1999) In: Abstracts of the 12th international carotenoid symposium, Cairns, Australia, 18–23 July 1999 Google Scholar
  32. 32.
    Bendich A (1989) In: Krinsky NI, Mathews-Roth MM, Taylor RF (eds) Carotenoids: chemisty and biology. Plenum, New York London, p 323 Google Scholar
  33. 33.
    Khachik F, Steck A, Pfander H (1977) In: Ohigashi H, Osawa T, Terao J, Watanabe S, Yoshikawa T (ed) Food factors for cancer prevention. Springer, Tokyo, p 542 Google Scholar
  34. 34.
    Knekt P, Järvinen R, Teppo L, Aromaa A, Seppänen R (1999) J Natl Cancer Inst 91:182 CrossRefGoogle Scholar
  35. 35.
    Murakami A, Nakashima M, Koshiba T, Maoka T, Nishino H, Yano M, Sumida T, Kim OK, Koshimizu K, Ohigashi H (2000) Cancer Lett 149:115 CrossRefGoogle Scholar
  36. 36.
    Maoka T, Mochida K, Kozuka M, Ito Y, Fujiwara Y, Hashimoto K, Enjo F, Ogata M, Nobukuni Y, Tokuda H, Nishino H (2001) Cancer Lett 172:103 CrossRefGoogle Scholar
  37. 37.
    Diwadkar-Navsariwala V, Novotny JA, Gustin DM, Sosman JA, Stacewicz-Sapuntzakis M, Murray JL, Tiller PA, Bowen PE (2002) In: Abstracts of the 13th international carotenoid symposium, Honolulu, USA, 6–11 January 2002 Google Scholar
  38. 38.
    Bobrowska-Hägerstrand M, Wróbel A, Rychlik B, Bartosz G, Söderström T, Shirataki Y, Motohashi N, Molnár J, Michalak K, Hägerstrand H (2001) Blood Cells Mol Dis 27:894 CrossRefGoogle Scholar
  39. 39.
    Mayne ST (2002) 13th International Carotenoid Symposium January 6–11, Honolulu, USA, abstracts, p 10 Google Scholar
  40. 40.
    Kim HS, Christov K, Chen L, Ghosh L, Duncan C, Sharifi R, Bowen P (2002) In: Abstracts of the 13th international carotenoid symposium, Honolulu, USA, 6–11 January 2002 Google Scholar
  41. 41.
    Hirsch K, Sharoni Y, Danilenko M, Giat Y, Kirilov E, Nahum A, Levy J (2002) In: Abstracts of the 13th international carotenoid symposium, Honolulu, USA, 6–11 January 2002 Google Scholar
  42. 42.
    Ugocsai K, Varga A, Molnár P, Antus S, Molnár J (2005) In Vivo 19:433 Google Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2008

Authors and Affiliations

  • Joseph Molnár
    • 1
  • Helga Engi
    • 1
  • Nóra Gyémánt
    • 1
  • Zsuzsanne Schelz
    • 1
  • Gabriella Spengler
    • 1
  • Imre Ocsovski
    • 1
  • Miklós Szücs
    • 1
  • Judith Hohmann
    • 2
  • Margaret Szabo
    • 3
  • Lajos Tanács
    • 4
  • Péter Molnár
    • 5
  • Joseph Deli
    • 6
  • Liselotte Krenn
    • 7
  • Masami Kawase
    • 8
  • Hidetsugu Wakabayashi
    • 9
  • Teruo Kurihara
    • 9
  • Yoshiaki Shirataki
    • 10
  • Hiroshi Sakagami
    • 11
  • Noboru Motohashi
    • 12
  • Remigijus Didiziapetris
    • 13
  1. 1.Institute of Medical Microbiology and ImmunologyUniversity of SzegedSzegedHungary
  2. 2.Department of PharmacognosyUniversity of SzegedSzegedHungary
  3. 3.Department of Plant PhysiologyUniversity of SzegedSzegedHungary
  4. 4.Department of Food Chemistry, Faculty of EngineeringUniversity of SzegedSzegedHungary
  5. 5.Department of PharmacognosyUniversity of Pécs, Medical SchoolPécsHungary
  6. 6.Department of Biochemistry and Medical ChemistryUniversity of Pécs, Medical SchoolPécsHungary
  7. 7.Department of PharmacognosyPharmaCenter Vienna, University of ViennaViennaAustria
  8. 8.Faculty of Pharmaceutical SciencesMatsuyama UniversityEhimeJapan
  9. 9.Faculty of SciencesJosai UniversitySaitamaJapan
  10. 10.Faculty of Pharmaceutical SciencesJosai UniversitySaitamaJapan
  11. 11.Division of Pharmacology, Department of Diagnostic and Therapeutic SciencesMeikai University School of DentistrySaitamaJapan
  12. 12.Meiji Pharmaceutical UniversityTokyoJapan
  13. 13.Pharma Algorythms, Inc.VilniusLithuania

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