Down-regulation of the erbB-2 receptor by trastuzumab (herceptin) enhances tumor necrosis factor-related apoptosis-inducing ligand-mediated apoptosis in breast and ovarian cancer cell lines that overexpress erbB-2
| Autor: | M, Cuello, S A, Ettenberg, A S, Clark, M M, Keane, R H, Posner, M M, Nau, P A, Dennis, S, Lipkowitz |
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| Rok vydání: | 2001 |
| Předmět: |
Ovarian Neoplasms
Membrane Glycoproteins Receptor ErbB-2 Tumor Necrosis Factor-alpha Recombinant Fusion Proteins Antibodies Monoclonal Down-Regulation Antineoplastic Agents Apoptosis Breast Neoplasms Drug Synergism Protein Serine-Threonine Kinases Trastuzumab Antibodies Monoclonal Humanized TNF-Related Apoptosis-Inducing Ligand Proto-Oncogene Proteins Tumor Cells Cultured Humans Female Apoptosis Regulatory Proteins Proto-Oncogene Proteins c-akt |
| Zdroj: | Cancer research. 61(12) |
| ISSN: | 0008-5472 |
| Popis: | We investigated whether combined treatment with tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and trastuzumab could enhance the specific killing of cells that overexpress the erbB-2 receptor. The combination resulted in an enhancement of TRAIL-mediated apoptosis in all cell lines overexpressing erbB-2 receptor compared with either reagent alone. In contrast, there was no effect in cell lines with low levels of the erb-B2 receptor. Trastuzumab treatment resulted in down-regulation of the erbB-2 receptor in all erbB-2-overexpressing cell lines. Similar enhancement of TRAIL toxicity was observed when the erbB-2 receptor was down-regulated using antisense oligodeoxynucleotides. Down-regulation of the erbB-2 receptor protein by trastuzumab or antisense oligodeoxynucleotides decreased Akt kinase activation but not mitogen-activated protein kinase activation. Down-regulation of Akt kinase activity by a phosphatidylinositol 3'-kinase inhibitor (LY294002) also resulted in enhancement of TRAIL-mediated apoptosis. Expression of a constitutively active form of Akt kinase in an erbB-2-overexpressing cell line completely abrogated the increase in TRAIL-mediated apoptosis by trastuzumab and significantly reduced the biological effect of either reagent alone. Therefore, down-regulation of the erbB-2 receptor by trastuzumab enhances TRAIL-mediated apoptosis by inhibiting Akt kinase activity. These data suggest that the combination of trastuzumab and TRAIL may allow enhanced therapeutic efficacy and specificity in the treatment of erbB-2-overexpressing tumors. |
| Databáze: | OpenAIRE |
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