Decreased production of vascular endothelial growth factor in adriamycin-resistant breast cancer cells.

MCF-7/ADR cells, a doxorubicin-resistant human breast cancer cell line, have acquired resistance to several anti-cancer chemotherapeutic agents, such as anthracyclines and taxol. Here, we found that MCF-7/ADR cells produced lower levels of vascular endothelial growth factor (VEGF) than control MCF-7 cells. Molecular analyses using Western blots and reporter constructs containing either the human VEGF promoter or a minimal promoter for the transcription factor, hypoxia-inducible factor-1 (HIF-1), supported the involvement of HIF-1alpha in the down-regulation of VEGF transcription in MCF-7/ADR cells. In addition, the basal activities of Akt and GSK-3beta were deregulated in MCF-7/ADR cells, and either the activation of PI3-kinase or the inhibition of GSK-3 restored the diminished transcription of VEGF. Chick chorioallantoic membrane (CAM) assay finally confirmed that angiogenesis intensity in MCF-7/ADR cells was significantly decreased compared with that in control MCF-7 cells.