Zoledronate Sensitizes Endothelial Cells to Tumor Necrosis Factor-induced Programmed Cell Death

Abstract

Bisphosphonates are potent inhibitors of osteoclast function widely used to treat conditions of excessive bone resorption, including tumor bone metastases. Recent evidence indicates that bisphosphonates have direct cytotoxic activity on tumor cells and suppress angiogenesis, but the associated molecular events have not been fully characterized. In this study we investigated the effects of zoledronate, a nitrogen-containing bisphosphonate, and clodronate, a non-nitrogen-containing bisphosphonate, on human umbilical vein endothelial cell (

Bisphosphonates and Cancer-Induced Bone Disease: Beyond Their Antiresorptive Activity

“…Failure of the small GTPase Ras to translocate to the plasma membrane in zoledronate-treated cancer cells has been reported (2,3,10). This leads to the inhibition of the downstream Ras/Raf-1/MEK/ERK1-2 mitogenic and pKB/Akt antiapoptotic pathways in these cells, and to the subsequent activation of caspases (2,5). The antiproliferative effects of NBPs are, however, not always the result of apoptotic cell death.…”

“…Indeed, NBPs can act directly on endothelial cells that are part of the stroma surrounding the tumor. They reduce endothelial cell adhesion and proliferation, and decrease capillary-like tube formation (2,3,5,9). They also inhibit the formation of blood vessels in different animal models of angiogenesis (2,3).…”

“…Moreover, minodronate (9) and zoledronate (14) impair the growth of melanomas and cervical carcinomas in animals, respectively, by suppressing tumor-associated angiogenesis. These observations (2,3,5,9,14), taken together with the fact that NBPs decrease circulating levels of vascular endothelial growth factor in metastatic cancer patients (2), raise the exciting possibility that NBPs could be potent antiangiogenic agents.…”

Distinctive role of integrin-mediated adhesion in TNF-induced PKB/Akt and NF-κB activation and endothelial cell survival

“…HUVEC culture, electroporation and adenoviral infection HUVEC were prepared, cultured and electroporated as described (Bezzi et al, 2003). AdNI-kB-or AdLacZ-infected HUVEC (100 multiplicity of infection (MOI)) were used 24 h postinfection.…”

Underlying Mechanisms and Therapeutic Strategies for Bisphosphonate-Related Osteonecrosis of the Jaw (BRONJ)

“…Indeed, N-BPs exhibit cytotoxicity in vitro not only against osteoclasts but also against a variety of other cells 48) and Zol has been reported to augment the cytotoxic effect of TNF against vascular endothelial cells. 49,50) As described in Section 4.1., N-BPs induce HDC in various tissues in mice and also augment HDC-induction by LPS, and vascular endothelial cells are supposed to be the major cells in which HDC is induced. 26,51) Thus, inhibition of FPP synthase results in toxic effects via a variety of effects on a variety of cells.…”