Tubular morphogenesis by genotoxic therapeutic agents that induce NF-kappaB activation in human vascular endothelial...

Angiogenic stimuli induce tubular morphogenesis and angiogenesis in vascular endothelial cells, but these cells are highly vulnerable to cytokines, oxidative stress, and genotoxic anticancer agents. A transcription factor, NF-kappaB, is involved in the protection against apoptosis and in angiogenesis in response to stimuli that could induce cell death. NF-kappaB was specifically activated by the genotoxic anticancer therapeutic agents etoposide and doxorubicin, but not by bleomycin, mitomycin C and cisplatin, in human vascular endothelial cells in three independent assay systems: nuclear translocation of NF-kappaB, binding of NF-kappaB to its consensus sequence, and NF-kappaB -dependent transcription. Exposure to etoposide and doxorubicin induced tubular morphogenesis by vascular endothelial cells in type I collagen gel at rates comparable to tumor necrosis factor-alpha. Co-administration of NF-kappaB antisense oligonucleotides inhibited the angiogenesis by doxorubicin and etoposide. In contrast, bleomycin, mitomycin C, and cisplatin did not induce angiogenesis. An angiogenic factor, interleukin 8, was dramatically induced in vascular endothelial cells treated with doxorubicin, but not in cells treated with cisplatin. Co-administration of anti-interleukin 8 antibody almost completely blocked the doxorubicin-induced angiogenesis in vitro, suggesting a paracrine/autocrine control through drug-induced angiogenic factor(s). The presence or absence of NF-kappaB activation may have an essential role in tubular morphogenesis by vascular endothelial cells during chemotherapeutic treatment, possibly through interleukin 8.