In vitro characterization of the anticancer activity of membrane-active cationic peptides. I. Peptide-mediated cytotoxicity and peptide-enhanced cytotoxic activity of doxorubicin against wild-type and p-glycoprotein over-expressing tumor cell lines

Authors: Johnstone S.¹; Gelmon K.; Mayer L.; Hancock R.²; Bally M.

Source: Anti-Cancer Drug Design, Volume 15, Number 2, 2000 , pp. 151-160(10)

Publisher: Cognizant Communication Corporation

Abstract:

Cationic amphiphathic peptides, such as the defensins and cecropins, induce cell death in prokaryotic and eukaryotic cells by increasing membrane permeability. Increased permeability may lead to cell lysis or, alternatively, may produce subtle changes in the membrane's barrier function that promote cell death. The In vitro cytotoxic and lytic activity of short mammalian-derived extended-helical cationic peptides and insect-derived alpha-helical peptides was measured in this study with the objective of establishing the anticancer potential of these agents. Two specific aims were addressed: (1) to assess the activity of peptides against non-malignant cells (sheep erythrocytes and human umbilical vein endothelial cells) versus tumor cells; and (ii) to characterize the cytotoxic activity using multidrug-resistant tumor cell lines in the presence and absence of the anthracycline doxorubicin. Cell lysis assays demonstrated that the lytic activity of the peptides tested was 2->50 times more cytotoxic to tumor cells than to non-malignant cells. Further, the cytotoxic activity of these peptides was equivalent when tested against sensitive and multidrug-resistant cell lines. In addition to their inherent cytotoxic activity, these membrane-active peptides can also augment the In vitro cytotoxic activity of doxorubicin against multidrug-resistant tumor cells.

Keywords: amphipathic peptides; cytotoxicity; membrane permeability; multidrug resistance; p-glycoprotein

Document Type: Research article

Affiliations: 1: Corresponding author 2: Department of Microbiology and Immunology, University of British Columbia, 6174 University Blvd, Vancouver, BC, Canada

Publication date: 2000-04-01

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