Dexniguldipine-HCl is a potent allosteric inhibitor of [3H]vinblastine binding to P-glycoprotein of CCRF ADR 5000 cells

Eur J Pharmacol. 1994 Dec 15;288(1):105-14. doi: 10.1016/0922-4106(94)90015-9.


Cell membranes were prepared from the multidrug resistant, P-glycoprotein expressing human lymphoblastoid cell line CCRF-ADR 5000. The P-glycoprotein of these membranes possessed high affinity binding sites for [3H]vinblastine, with a Kd of 8 +/- 2 nM and Bmax of 17 +/- 8 pmol/mg of protein. The binding of [3H]vinblastine to P-glycoprotein was not ATP-dependent, and was inhibited by cytotoxic drugs with the following potency order; vincristine > doxorubicin > etoposide. The 1,4-dihydropyridine and multidrug resistance reversing agent, dexniguldipine-HCl, inhibited binding with a Ki value of 37 nM. The multidrug resistance reversing agent cyclosporin A, and the cytotoxics doxorubicin and etoposide did not alter the kinetics of [3H]vinblastine dissociation from P-glycoprotein; however, the 1,4-dihydropyridines dexniguldipine-HCl and nicardipine accelerated dissociation of [3H]vinblastine. These data suggest that P-glycoprotein possesses at least two allosterically coupled drug acceptor sites; receptor site 1 which binds vinblastine, doxorubucin, etoposide and cyclosporin A, and receptor site 2 which binds dexniguldipine-HCl and other 1,4-dihydropyridines.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / metabolism*
  • Allosteric Regulation
  • Binding, Competitive / drug effects
  • Calcium Channel Blockers / pharmacology*
  • Cell Division / drug effects
  • Cyclosporine / pharmacology
  • Dihydropyridines / pharmacology*
  • Doxorubicin / pharmacology
  • Drug Resistance, Multiple
  • Etoposide / pharmacology
  • Humans
  • Kinetics
  • Mathematics
  • Precursor Cell Lymphoblastic Leukemia-Lymphoma / pathology
  • Tritium / metabolism
  • Tumor Cells, Cultured
  • Vinblastine / metabolism*
  • Vincristine / pharmacology


  • ATP Binding Cassette Transporter, Subfamily B, Member 1
  • Calcium Channel Blockers
  • Dihydropyridines
  • Tritium
  • Vincristine
  • Vinblastine
  • Etoposide
  • Doxorubicin
  • Cyclosporine
  • niguldipine