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Journal of Natural Medicines

, Volume 73, Issue 1, pp 226–235 | Cite as

Selective inhibition of P-gp transporter by goniothalamin derivatives sensitizes resistant cancer cells to chemotherapy

  • Julia Sachs
  • Onat Kadioglu
  • Anja Weber
  • Vanessa Mundorf
  • Janina Betz
  • Thomas Efferth
  • Jörg Pietruszka
  • Nicole TeuschEmail author
Note

Abstract

Overexpression of efflux transporters of the ATP-binding cassette (ABC) transporter family, primarily P-glycoprotein (P-gp), is a frequent cause of multidrug resistance in cancer and leads to failure of current chemotherapies. Thus, identification of selective P-gp inhibitors might provide a basis for the development of novel anticancer drug candidates. The natural product goniothalamin and 21 derivatives were characterized regarding their ability to inhibit ABC transporter function. Among the goniothalamins, selective inhibitors of P-gp were discovered. The two most potent inhibitors (R)-3 and (S)-3 displayed the ability to increase intracellular accumulation of doxorubicin, thereby sensitizing P-gp-overexpressing tumor cells to chemotherapy by decreasing doxorubicin IC50 value up to 15-fold. Molecular docking studies indicated these compounds to inhibit P-gp by acting as transporter substrates. In conclusion, our findings revealed a novel role of goniothalamin derivatives in reversing P-gp-mediated chemotherapy resistance.

Keywords

Goniothalamin Multidrug resistance P-glycoprotein Cancer chemotherapy Resistance reversal 

Abbreviations

ABC

ATP-binding cassette

BCRP

Breast cancer resistance protein

DMSO

Dimethylsulfoxide

MDR

Multidrug resistance

MRP1

Multidrug resistance-associated protein 1

P-gp

P-glycoprotein

SAR

Structure–activity relationship

Notes

Acknowledgements

We would like to thank Dr. Erasmus Schneider (Wadsworth Center, New York State Department of Health, Albany, NY, USA) for kindly providing the MCF-7/MX cells.

Funding

This work was funded by the German Federal Ministry for Economic Affairs and Energy (‘ZIM Kooperationsprojekt’ KF3279X01AJ3) and A.W. was supported by a scholarship of the Studienstiftung des deutschen Volkes. The PhD training of J.S. was financed by the graduate program in Pharmacology and Experimental Therapeutics at the University of Cologne, which is financially and scientifically supported by Bayer.

Compliance with ethical standards

Conflict of interests

The authors declare that they have no conflict of interest.

Supplementary material

11418_2018_1230_MOESM1_ESM.docx (37 kb)
Supplementary material 1 (DOCX 37 kb)

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Copyright information

© The Japanese Society of Pharmacognosy and Springer Japan KK, part of Springer Nature 2018

Authors and Affiliations

  • Julia Sachs
    • 1
  • Onat Kadioglu
    • 2
  • Anja Weber
    • 3
  • Vanessa Mundorf
    • 1
  • Janina Betz
    • 1
  • Thomas Efferth
    • 2
  • Jörg Pietruszka
    • 3
    • 4
  • Nicole Teusch
    • 1
    Email author
  1. 1.Bio-Pharmaceutical Chemistry and Molecular Pharmacology, Faculty of Applied Natural SciencesTechnische Hochschule Köln, CHEMPARKLeverkusenGermany
  2. 2.Department of Pharmaceutical Biology, Institute of Pharmacy and BiochemistryJohannes Gutenberg Universität MainzMainzGermany
  3. 3.Institute of Bioorganic ChemistryHeinrich-Heine-Universität Düsseldorf Im Forschungszentrum JülichJülichGermany
  4. 4.IBG-1: Biotechnology, Forschungszentrum JülichJülichGermany

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