Herceptin Down-Regulates HER-2/neu and Vascular Endothelial Growth Factor Expression and Enhances Taxol-Induced Cytotoxicity of Human Ewing's Sarcoma Cells In vitro and In vivo

Abstract

We have previously shown that high levels of HER-2/neu protein were overexpressed in human Ewing's sarcoma cells (TC71, SK-ES1) relative to normal human osteoblasts. The purpose of this study was to determine whether herceptin alone or in combination with chemotherapeutic agents could inhibit the growth of Ewing's sarcoma in vitro and in vivo. Western blot analysis showed that the protein levels of HER-2/neu were decreased following herceptin treatment. Cell growth was also inhibited by herceptin in a dose-dependent manner with an IC 50 of 4 mg/mL in TC71 and SK-ES1 cell line, whereas human immunoglobin had no effect. Northern blot and ELISA showed the RNA expression and protein levels of vascular endothelial growth factor were also inhibited by herceptin treatment with no alteration in HIF-1A protein and topoisomerase IIA expression. Furthermore, Ewing's sarcoma tumor growth was significantly delayed by 100 mg/kg herceptin treatment in our Ewing's sarcoma xenograft mouse model. Combining taxol with herceptin resulted in additive cytotoxicity, whereas herceptin-etoposide, doxorubicin, and 9-nitrocamptothecin combinations did not. Taxol-herceptin enhanced growth inhibition in TC71 cells in vitro compared with either agent alone. Ewing's sarcoma growth was also delayed in vivo and mean tumor size was significantly lower in mice treated with herceptin plus taxol than in those receiving taxol or herceptin alone. These data suggest that herceptin in combination with taxol may be a therapeutic option in the treatment of Ewing's sarcoma.

Antibodies targeted to TRAIL receptor-2 and ErbB-2 synergize in vivo and induce an antitumor immune response

“…1E), it did not affect hypoxia-inducible factor 1␣ (HIF-1␣) expression in vivo ( Fig. 4B; consistent with other studies) (20). In contrast, MD5-1 significantly decreased HIF-1␣ expression in ErbB-2/neuT tumors (Fig.…”

HER2/neu: an increasingly important therapeutic target. Part 2: Distribution of HER2/neu overexpression and gene amplification by organ, tumor site and histology

“…HER2/neu is overexpressed in >40% of osteosarcomas [275,305], but is not a valid target in Ewings sarcoma [299,304,306] (consistent with the data above pertaining to lack of HER2/neu expression or overexpression in peripheral neuroendocrine tissues and tumors), chondrosarcomas or desmoid tumors [307]. There is a single, remote, unconfirmed report of non-AIDs related Kaposi's sarcoma having significant HER2/neu expression [308].…”

Regulation of Cell Proliferation and Migration by Keratin19-Induced Nuclear Import of Early Growth Response-1 in Breast Cancer Cells

“…In HER2-positive MCF7 HER2, BT474, and SKBR3 cells, the activities of c-Raf/mitogenactivated protein kinase (MAPK)-ERK kinase (MEK), ERK, and Elk were downregulated by KRT19 silencing, as determined by their phosphorylation status, whereas activities of c-Raf/MEK/ERK/Elk in HER2-negative/low T47D, and MCF7 vec cells were not significantly changed after KRT19 silencing. Needless to say, activation of the ERK pathway in HER2-negative/low cells was achieved by a HER2-independent mechanism, whereas that of HER2-positive cells was HER2 dependent (21,22). Downregulation of HER2 by KRT19 silencing (Fig.…”