Cytotoxicity of the novel anti-cancer drug rViscumin depends on HER-2 levels in SKOV-3 cells.

Abstract

rViscumin is a recombinant mistletoe lectin under clinical investigation as new anti-cancer drug. The relationship between oncogene, e.g., HER-2/neu (c-erbB2) receptor activation and tumor cell chemosensitivity, is of considerable importance to better predict the response to chemotherapy. Here, we analyze the cellular and molecular effects of HER-2 expression on rViscumin chemotoxicity in SKOV-3 cells. We show that selective depletion of HER-2 by ribozyme-targeting markedly decreases cellular sensitivity towards rViscumin. These findings are confirmed by treatment with the well-established inhibitory HER-2 antibody trastuzumab (Herceptin). Using clonal ribozyme-transfected cell lines, we establish a 'HER-2 gene dose' dependence of rViscumin cytotoxicity, which is due to differential induction of apoptosis and is not mediated by cell cycle alterations or altered cellular rViscumin binding/internalization. We further demonstrate an rViscumin-mediated, HER-2-dependent down-regulation of bcl-2 and the dose-dependent activation of members of the MAPK family, p42/44, SAPK/JNK, and p38, but not of caspases-3 and -7.

• Authors: Shaker Abuharbeid, Jürgen Apel, Martin Sander, Babette Fiedler, Martin Langer, Mary-Lou Zuzarte, Frank Czubayko, Achim Aigner
• Journal: Biochemical and biophysical research communications (Biochem Biophys Res Commun) Vol. 321 Issue 2 Pg. 403-12 (Aug 20 2004) ISSN: 0006-291X [Print] United States
• PMID: 15358191 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antibodies, Monoclonal
• Antibodies, Monoclonal, Humanized
• Antineoplastic Agents
• Plant Preparations
• Plant Proteins
• Proto-Oncogene Proteins c-bcl-2
• Ribosome Inactivating Proteins, Type 2
• Toxins, Biological
• ribosome inactivating protein, Viscum
• Receptor, ErbB-2
• Trastuzumab

Topics

• Antibodies, Monoclonal (pharmacology)
• Antibodies, Monoclonal, Humanized
• Antineoplastic Agents (metabolism, pharmacology, toxicity)
• Apoptosis (drug effects)
• Cell Line, Tumor
• Down-Regulation (drug effects)
• Female
• Gene Expression Regulation, Neoplastic (drug effects)
• Humans
• Inhibitory Concentration 50
• MAP Kinase Signaling System (drug effects)
• Ovarian Neoplasms (drug therapy, metabolism, pathology)
• Plant Preparations (metabolism, pharmacology, toxicity)
• Plant Proteins (metabolism, pharmacology, toxicity)
• Proto-Oncogene Proteins c-bcl-2 (metabolism)
• Receptor, ErbB-2 (antagonists & inhibitors, metabolism)
• Ribosome Inactivating Proteins, Type 2
• Toxins, Biological (metabolism, pharmacology, toxicity)
• Trastuzumab