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Phorbol esters induce multidrug resistance in human breast cancer cells

R L Fine1, J Patel, B A Chabner

  • 1Clinical Pharmacology Branch, National Cancer Institute, Bethesda, MD 20892.

Proceedings of the National Academy of Sciences of the United States of America
|January 1, 1988
PubMed

Insights

Protein kinase C (PKC) activity is elevated in multidrug-resistant (MDR) cancer cells. Stimulating PKC induces MDR, suggesting its role in drug efflux pump modulation.

Area of Science:

  • Biochemistry
  • Cell Biology
  • Pharmacology

Background:

  • Mechanisms of multidrug resistance (MDR) in cancer are not fully understood.
  • Agents that reverse MDR, like verapamil, inhibit protein kinase C (PKC).
  • PKC's role in MDR requires further investigation.

Purpose of the Study:

  • To investigate the role of protein kinase C (PKC) in multidrug resistance (MDR) in human breast cancer cells.
  • To determine if PKC stimulation can induce or enhance a drug-resistant phenotype.
  • To explore the relationship between PKC activity, drug accumulation, and resistance.

Main Methods:

  • Assayed PKC activity in multidrug-resistant and sensitive human breast cancer cell lines.
  • Exposed cells to phorbol ester (P(BtO)2) to stimulate PKC and observed effects on drug resistance.
  • Measured intracellular accumulation of doxorubicin and vincristine, and protein phosphorylation.
  • Assessed the reversibility of induced resistance using verapamil and trifluoperazine.

Main Results:

  • PKC activity was 7-fold higher in MDR cells compared to sensitive cells.
  • P(BtO)2 stimulation increased PKC activity and induced a drug-resistant phenotype in sensitive cells.
  • PKC stimulation decreased intracellular doxorubicin and vincristine accumulation, suggesting increased efflux.
  • Induced resistance was partially reversed by verapamil and trifluoperazine.

Conclusions:

  • Stimulation of protein kinase C (PKC) plays a significant role in mediating drug transport changes associated with multidrug resistance (MDR).
  • PKC may modulate MDR efflux pumps through protein phosphorylation.
  • Targeting PKC could be a strategy to overcome drug resistance in cancer therapy.

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