Cytotoxicity of the novel anti-cancer drug rViscumin depends on HER-2 levels in SKOV-3 cells.
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.
Abuharbeid
Shaker
S
Department of Pharmacology and Toxicology, Philipps-University School of Medicine, Marburg, Germany.
Apel
Jürgen
J
Sander
Martin
M
Fiedler
Babette
B
Langer
Martin
M
Zuzarte
Mary-Lou
ML
Czubayko
Frank
F
Aigner
Achim
A
D000911:Antibodies, Monoclonal / Q000494:pharmacology; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents / Q000378:metabolism / Q000494:pharmacology* / Q000633:toxicity; D017209:Apoptosis / Q000187:drug effects*; D045744:Cell Line, Tumor; D015536:Down-Regulation / Q000187:drug effects; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D020128:Inhibitory Concentration 50; D020935:MAP Kinase Signaling System / Q000187:drug effects; D010051:Ovarian Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D028321:Plant Preparations / Q000378:metabolism / Q000494:pharmacology* / Q000633:toxicity; D010940:Plant Proteins / Q000378:metabolism / Q000494:pharmacology* / Q000633:toxicity; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D054790:Ribosome Inactivating Proteins, Type 2; D014118:Toxins, Biological / Q000378:metabolism / Q000494:pharmacology* / Q000633:toxicity; D000068878:Trastuzumab
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D028321:Plant Preparations; D010940:Plant Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D018719:Erb-b2 Receptor Tyrosine Kinases; D054790:Ribosome Inactivating Proteins, Type 2; D014118:Toxins, Biological; D000068878:Trastuzumab; C009674:ribosome inactivating protein, Viscum