Bioactive Heterocycles VI pp 133-159

Part of the Topics in Heterocyclic Chemistry book series (TOPICS, volume 15) | Cite as

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
Chapter

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.

Anthocyanins Flavonoids Carotenoids Isoflavones Multidrug resistance reversal  

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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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