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Pharmaceutical Research

, Volume 26, Issue 1, pp 182–188 | Cite as

Impact of Novel MDR Modulators on Human Cancer Cells: Reversal Activities and Induction Studies

  • Claudius Coburger
  • Hermann Lage
  • Josef Molnár
  • Andreas HilgerothEmail author
Research Paper

Abstract

Purpose

Novel multidrug resistance (mdr) modulators have been proved as inhibitors of P-glycoprotein (P-gp). We first investigated the in vitro effects of selected compounds in human cancer cells on multidrug resistance reversal effects compared to drug standards and on P-gp induction to characterize the potential of the compounds as clinical candidates.

Methods

The uptake of daunorubicin into a parental cancer cell line and P-gp expressing subcell line in presence of the modulators was characterized by flow cytometry. Induction of P-gp was investigated in P-gp expressing and non-expressing cancer cell lines on the RNA level by real-time quantitative polymerase chain reaction (RTQ-PCR) and protein quantification. Results were additionally confirmed by northern blot techniques and functionality assays in selected cell lines.

Results

The novel modulators showed activities as mdr reversers in a P-gp specific human cancer cell model with mainly increased uptake rates of daunorubicin into the drug-resistant cell line. H17 proved to be more active than cyclosporine A as a known strong mdr modulator. The induction studies revealed practically no induction potential of the compounds in usual short-time drug application regimes in all cell lines. Furthermore, the novel modulators did not increase the efflux of a P-gp model substrate in the functionality model assay. This confirmed the results of non-P-gp induction which was observed on both the RNA and the protein levels.

Conclusions

The novel mdr modulators proved as perspective candidates for further clinical studies because they turned out to be highly active in human cancer cell models. Furthermore, they showed no potential to induce the transmembrane efflux pump P-gp. This is a significant advantage compared to modulators which failed in clinical trials because of induction-effects that increase cellular resistances and, moreover, side effects in normal cells.

KEY WORDS

flow cytometry induction studies mdr modulators P-glycoprotein reversal effects 

Notes

Acknowledgements

The work was financially supported by the EU within the COSTB16 action, the BMBF within a bilateral DAAD exchange program and the DFG within the projects HI 687/5-1 and LA 1039/5-1.

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Copyright information

© Springer Science+Business Media, LLC 2008

Authors and Affiliations

  • Claudius Coburger
    • 1
  • Hermann Lage
    • 2
  • Josef Molnár
    • 3
  • Andreas Hilgeroth
    • 1
    Email author
  1. 1.Institute of PharmacyMartin-Luther University Halle-WittenbergHalleGermany
  2. 2.Institute of PathologyUniversity Hospital CharitéBerlinGermany
  3. 3.Department of Medical MicrobiologyUniversity of SzegedSzegedHungary

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