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Investigational New Drugs

, Volume 31, Issue 3, pp 587–598 | Cite as

Gambogic acid is cytotoxic to cancer cells through inhibition of the ubiquitin-proteasome system

  • Jenny Felth
  • Karolina Lesiak-Mieczkowska
  • Padraig D’Arcy
  • Caroline Haglund
  • Joachim Gullbo
  • Rolf Larsson
  • Stig Linder
  • Lars Bohlin
  • Mårten Fryknäs
  • Linda RickardsonEmail author
PRECLINICAL STUDIES

Summary

Gambogic acid (GA), displays cytotoxicity towards a wide variety of tumor cells and has been shown to affect many important cell-signaling pathways. In the present work, we investigated the mechanism of action of GA by analysis of drug-induced changes in gene expression profiles and identified GA and the derivative dihydro GA as possible inhibitors of the ubiquitin-proteasome system (UPS). Both GA and dihydro GA inhibited proteasome function in cells resulting in the accumulation of polyubiquitin complexes. In vitro experiments showed that both GA and dihydro GA inhibited 20S chymotrypsin activity and the inhibitory effects of GA and dihydro GA on proteasome function corresponded with apoptosis induction and cell death. In conclusion, our results show that GA and dihydro GA exert their cytotoxic activity through inhibition of the UPS, specifically by acting as inhibitors of the chymotrypsin activity of the 20S proteasome.

Keywords

Gambogic acid Ubiquitin-proteasome system Proteasome inhibition 20S chymotrypsin activity Cytotoxicity 

Notes

Acknowledgments

The authors are very grateful to Professor Nico Dantuma for the kind gift of MelJuSo UbG76V-YFP cells. We also wish to thank Maria Rydåker, Anna Haukkula and Hanna Göransson Kultima at the Uppsala Array Platform for microarray analysis, Sandra Erlund for assistance in the literature survey, and Lena Lenhammar for RNA preparation. This work was supported by unconditional grants from the Lions Cancer Research Fund and a Swedish Institute scholarship for Karolina Lesiak-Mieczkowska.

Conflict of interest

The authors declare that they have no conflict of interest.

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Copyright information

© Springer Science+Business Media New York 2012

Authors and Affiliations

  • Jenny Felth
    • 1
  • Karolina Lesiak-Mieczkowska
    • 2
  • Padraig D’Arcy
    • 2
  • Caroline Haglund
    • 3
  • Joachim Gullbo
    • 3
  • Rolf Larsson
    • 3
  • Stig Linder
    • 2
  • Lars Bohlin
    • 1
  • Mårten Fryknäs
    • 3
  • Linda Rickardson
    • 3
    Email author
  1. 1.Division of Pharmacognosy, Department of Medicinal Chemistry, Biomedical CenterUppsala UniversityUppsalaSweden
  2. 2.Cancer Center Karolinska, Department of Oncology-PathologyKarolinska InstituteStockholmSweden
  3. 3.Division of Clinical Pharmacology, Department of Medical SciencesUppsala UniversityUppsalaSweden

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