Abstract
P-glycoprotein (PGP) is an energy-dependent efflux pump that serves to protect cells against the cytotoxicity of many natural product drugs including vinblastine (VBL). In this study we investigated the role of PGP in regulating initial VBL influx. The apparent influx of VBL, measured over the first 20 s, was 2-fold lower in KB-GRC1 cells expressing a transfected mdr1 gene at high level than in non-expressing parental KB-3-1 cells. Inhibition of PGP efflux function with dipyridamole increased the influx rate constant by 4.0-fold in the KB-GRC1 cells but only 2.1-fold in the KB-3-1 cells. Verapamil, another inhibitor of PGP-mediated efflux, increased the initial influx rate constant by 2.7-fold in the KB-GRC1 cells but only 1.4-fold in the KB-3-1 cells. Inhibition of PGP function by depletion of ATP increased influx by 6.8-fold and 2.2-fold in the two cell types, respectively. Mutation of PGP at both ATP binding sites abolished its ability to limit initial influx. Thus, VBL is serving as an efficient substrate for the efflux pump even within the first few seconds of drug exposure, consistent with the hypothesis that PGP may directly efflux drug from the cell membrane.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 24 print issues and online access
$259.00 per year
only $10.79 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Shalinsky, D., Jekunen, A., Alcaraz, J. et al. Regulation of initial vinblastine influx by P-glycoprotein. Br J Cancer 67, 30–36 (1993). https://doi.org/10.1038/bjc.1993.6
Issue Date:
DOI: https://doi.org/10.1038/bjc.1993.6
This article is cited by
-
Enhanced anticancer activity of combined treatment of imatinib and dipyridamole in solid Ehrlich carcinoma-bearing mice
Naunyn-Schmiedeberg's Archives of Pharmacology (2020)
-
Overcoming transporter-mediated multidrug resistance in cancer: failures and achievements of the last decades
Drug Delivery and Translational Research (2019)
-
The role of autologous transplantation in patients with multiple myeloma aged 65 years and over
Bone Marrow Transplantation (2000)
-
Acute lymphoblastic leukaemia-type intensive chemotherapy to eliminate minimal residual disease after high-dose melphalan and autologous transplantation in multiple myeloma – a phase I/II feasibility and tolerance study of 17 patients
Bone Marrow Transplantation (2000)
-
P-glycoprotein-mediated multidrug resistance in normal and neoplastic hematopoietic cells
Annals of Hematology (1994)