Effects of indole alkaloids on multidrug resistance and labeling of P-glycoprotein by a photoaffinity analog of vinblastine

William T. Beck, Margaret C. Cirtain, Constance J. Glover, Ronald L. Felsted, Ahmad Safa

Research output: Contribution to journalArticle

79 Citations (Scopus)

Abstract

Multidrug resistant cells are characterized by decreased drug accumulation and retention, thought to be mediated by a high molecular weight glycoprotein, P-glycoprotein (P-gp). Agents such as verapamil have been shown to increase anticancer drug cytotoxicity and increase the amount of drug accumulated and retained by such cells. We show here that in addition to verapamil, reserpine, chloroquine, quinine, quinacrine, yohimbine, vindoline, and catharanthine also enhance the cytotoxicity of vinblastine (VLB) in a multidrug resistant, human leukemic cell line, CEM/VLB1K, described here for the first time. These cells express P-gp as a doublet that is photoaffinity labeled by the analog of VLB, N(p-azido-[3-125I]salicyl)-N′-β-aminoethyvundesine ([125I]NASV). Both reserpine and, to a lesser extent, verapamil, compete with [125I]NASV for binding to P-gp. We also found that chloroquine, quinacrine, vindoline, and catharanthine, each of which enhanced VLB cytotoxicity in CEM/VLB1K cells by 10- to 15-fold, similarly inhibited [125I]NASV labeling of P-gp. However, neither quinine nor yohimbine inhibited this labeling, and the inhibition produced by catharanthine and vindoline was the greatest or exclusively on the lower band of the P-gp doublet. Our results suggest a complex relationship between the ability of a compound to modulate MDR and its ability to compete for binding to P-gp.

Original languageEnglish (US)
Pages (from-to)959-966
Number of pages8
JournalBiochemical and Biophysical Research Communications
Volume153
Issue number3
DOIs
StatePublished - Jun 30 1988
Externally publishedYes

Fingerprint

Indole Alkaloids
Vinblastine
Multiple Drug Resistance
P-Glycoprotein
Labeling
Cytotoxicity
Verapamil
Quinacrine
Quinine
Yohimbine
Reserpine
Chloroquine
Pharmaceutical Preparations
Glycoproteins
Molecular Weight
Molecular weight
Cells
Cell Line
vindoline
catharanthine

ASJC Scopus subject areas

  • Biochemistry
  • Biophysics
  • Molecular Biology

Cite this

Effects of indole alkaloids on multidrug resistance and labeling of P-glycoprotein by a photoaffinity analog of vinblastine. / Beck, William T.; Cirtain, Margaret C.; Glover, Constance J.; Felsted, Ronald L.; Safa, Ahmad.

In: Biochemical and Biophysical Research Communications, Vol. 153, No. 3, 30.06.1988, p. 959-966.

Research output: Contribution to journalArticle

Beck, William T. ; Cirtain, Margaret C. ; Glover, Constance J. ; Felsted, Ronald L. ; Safa, Ahmad. / Effects of indole alkaloids on multidrug resistance and labeling of P-glycoprotein by a photoaffinity analog of vinblastine. In: Biochemical and Biophysical Research Communications. 1988 ; Vol. 153, No. 3. pp. 959-966.
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