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.
Cationic amphipathic 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: (i) 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.
Johnstone
S A
SA
Division of Medical Oncology--Advanced Therapeutics, British Columbia Cancer Agency, Vancouver, Canada.
Gelmon
K
K
Mayer
L D
LD
Hancock
R E
RE
Bally
M B
MB
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics / Q000502:physiology*; D000595:Amino Acid Sequence; D000818:Animals; D000970:Antineoplastic Agents / Q000633:toxicity*; D001943:Breast Neoplasms; D002289:Carcinoma, Non-Small-Cell Lung; D002470:Cell Survival / Q000187:drug effects*; D004317:Doxorubicin / Q000633:toxicity*; D018432:Drug Resistance, Multiple; D004357:Drug Synergism; D005260:Female; D006461:Hemolysis / Q000187:drug effects; D006801:Humans; D020014:K562 Cells; D007941:Leukemia P388; D004915:Leukemia, Erythroblastic, Acute; D008175:Lung Neoplasms; D008224:Lymphoma, Follicular; D051379:Mice; D008969:Molecular Sequence Data; D009842:Oligopeptides / Q000737:chemistry / Q000633:toxicity; D010455:Peptides / Q000737:chemistry / Q000633:toxicity*; D017433:Protein Structure, Secondary; D012756:Sheep; D014407:Tumor Cells, Cultured
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000970:Antineoplastic Agents; D009842:Oligopeptides; D010455:Peptides; D004317:Doxorubicin