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

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Bioactive Heterocycles VI

Part of the book series: Topics in Heterocyclic Chemistry ((TOPICS,volume 15))

Abstract

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.

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Authors and Affiliations

  1. Institute of Medical Microbiology and Immunology, University of Szeged, Dóm tér 10, 6720, Szeged, Hungary

    Joseph Molnár, Helga Engi, Nóra Gyémánt, Zsuzsanne Schelz, Gabriella Spengler, Imre Ocsovski & Miklós Szücs

  2. Department of Pharmacognosy, University of Szeged, Eötvös u. 6., 6720, Szeged, Hungary

    Judith Hohmann

  3. Department of Plant Physiology, University of Szeged, Egyetem u.2., 6722, Szeged, Hungary

    Margaret Szabo

  4. Department of Food Chemistry, Faculty of Engineering, University of Szeged, Mars tér 7, 6725, Szeged, Hungary

    Lajos Tanács

  5. Department of Pharmacognosy, University of Pécs, Medical School, Rókus u. 2, 7624, Pécs, Hungary

    Péter Molnár

  6. Department of Biochemistry and Medical Chemistry, University of Pécs, Medical School, Szigeti út 12, 7624, Pécs, Hungary

    Joseph Deli

  7. Department of Pharmacognosy, PharmaCenter Vienna, University of Vienna, Althanstr. 14, 1090, Vienna, Austria

    Liselotte Krenn

  8. Faculty of Pharmaceutical Sciences, Matsuyama University, 4-2 Bunkyo-cho, Matsuyama-shi, 790-8578, Ehime, Japan

    Masami Kawase

  9. Faculty of Sciences, Josai University, 1-1 Keyakidai, Sakado-shi, 350-0295, Saitama, Japan

    Hidetsugu Wakabayashi & Teruo Kurihara

  10. Faculty of Pharmaceutical Sciences, Josai University, 1-1 Keyakidai, Sakado-shi, 350-0295, Saitama, Japan

    Yoshiaki Shirataki

  11. Division of Pharmacology, Department of Diagnostic and Therapeutic Sciences, Meikai University School of Dentistry, 1-1 Keyakidai, Sakado-shi, 350-0283, Saitama, Japan

    Hiroshi Sakagami

  12. Meiji Pharmaceutical University, 2-522-1 Noshio, Kiyose-shi, 204-8588, Tokyo, Japan

    Noboru Motohashi

  13. Pharma Algorythms, Inc., Mickeviviaus 29, 08117, Vilnius, Lithuania

    Remigijus Didiziapetris

Authors
  1. Joseph Molnár
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  2. Helga Engi
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  3. Nóra Gyémánt
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  4. Zsuzsanne Schelz
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  5. Gabriella Spengler
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  6. Imre Ocsovski
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  7. Miklós Szücs
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  8. Judith Hohmann
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  9. Margaret Szabo
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  10. Lajos Tanács
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  11. Péter Molnár
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  12. Joseph Deli
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  13. Liselotte Krenn
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  14. Masami Kawase
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  15. Hidetsugu Wakabayashi
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  16. Teruo Kurihara
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  17. Yoshiaki Shirataki
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  18. Hiroshi Sakagami
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  19. Noboru Motohashi
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  20. Remigijus Didiziapetris
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Corresponding author

Correspondence to Noboru Motohashi .

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Noboru Motohashi

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Molnár, J. et al. (2008). Multidrug Resistance Reversal on Cancer Cells by Selected Carotenoids, Flavonoids and Anthocyanins. In: Motohashi, N. (eds) Bioactive Heterocycles VI. Topics in Heterocyclic Chemistry, vol 15. Springer, Berlin, Heidelberg. https://doi.org/10.1007/7081_2008_120

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