Role of P-glycoprotein in dolastatin 10 resistance

Deborah L. Toppmeyer, Christopher A. Slapak, James Croop, Donald W. Kufe

Research output: Contribution to journalArticle

34 Scopus citations

Abstract

Dolastatin 10, a cytotoxic pentapeptide isolated from the mollusk Dolabella auricularia, exhibits potent antitumor activity. The present studies demonstrated that sublines of murine PC4 and human U-937 leukemia cells expressing a multidrug resistance (MDR) phenotype are cross-resistant to this agent. We also demonstrated that such resistance was reversed by verapamil. While these findings suggested the involvement of the P-glycoprotein (P-gp) in dolastatin 10 resistance, we performed similar studies in a CHO cell line transfected with the human mdr 1 cDNA. Expression of P-gp in the transfected cells was associated with resistance to dolastatin 10 by a verapamil-sensitive mechanism. The demonstration that photoaffinity labeling of P-gp was decreased in the presence of dolastatin 10 further supports the interaction of this cytotoxic peptide with P-gp. Taken together, these findings suggest that resistance to dolastatin 10 is conferred, at least in part, by P-gp and that this cytotoxic peptide is a novel member of the MDR phenotype.

Original languageEnglish (US)
Pages (from-to)609-612
Number of pages4
JournalBiochemical Pharmacology
Volume48
Issue number3
DOIs
StatePublished - Aug 3 1994
Externally publishedYes

Keywords

  • P-glycoprotein
  • cytotoxic peptides
  • dolastatin 10
  • multidrug resistance
  • peptide transport
  • tubulin binding drug

ASJC Scopus subject areas

  • Biochemistry
  • Pharmacology

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