Mechanism of inhibition of P-glycoprotein-mediated drug transport by protein kinase C blockers

Ariel F. Castro, Julie K. Horton, Carlos G. Vanoye, Guillermo A. Altenberg*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

43 Scopus citations


P-glycoprotein is a membrane ATPase that transports drugs out of cells and confers resistance to a variety of chemically unrelated drugs (multidrug resistance). P-glycoprotein is phosphorylated by protein kinase C (PKC), and PKC blockers reduce P-glycoprotein phosphorylation and increase drug accumulation. These observations suggest that phosphorylation of P- glycoprotein stimulates drug transport. However, there is evidence that PKC inhibitors directly interact with P-glycoprotein, and therefore the mechanism of their effects on P-glycoprotein-mediated drug transport and the possible role of phosphorylation in the regulation of P-glycoprotein function remain unclear. In the present work, we studied the effects of different kinds of PKC inhibitors on drug transport in cells expressing wild-type human P- glycoprotein and a PKC phosphorylation-defective mutant. We demonstrated that PKC blockers inhibit drug transport by mechanisms independent of P- glycoprotein phosphorylation. Inhibition by the blockers occurs by (i) direct competition with transported drugs for binding to P-glycoprotein, and (ii) indirect inhibition through a pathway that involves PKC inhibition, but is independent of P-glycoprotein phosphorylation. The effects of the blockers on P-glycoprotein phosphorylation do not seem to play an important role, but the PKC-signaling pathway regulates P-glycoprotein-mediated drug transport.

Original languageEnglish (US)
Pages (from-to)1723-1733
Number of pages11
JournalBiochemical Pharmacology
Issue number11
StatePublished - Dec 1 1999


  • ABC proteins
  • Chelerythrine
  • MDR1
  • Multidrug resistance
  • Phosphorylation
  • Safingol

ASJC Scopus subject areas

  • Biochemistry
  • Pharmacology


Dive into the research topics of 'Mechanism of inhibition of P-glycoprotein-mediated drug transport by protein kinase C blockers'. Together they form a unique fingerprint.

Cite this