Microvascular Endothelial Cell Responses in vitro and in vivo: Modulation by Zoledronic Acid and Paclitaxel?

Abstract

Background/Aims: The cytotoxic agent paclitaxel and the anti-resorptive drug zoledronic acid are used in the early and advanced breast cancer setting, respectively. Both agents have been demonstrated to have anti-tumour and anti-endothelial actions. Combining paclitaxel with zoledronic acid induces a synergistic increase in apoptotic breast cancer cell death in vitro, suggesting an increased anti-tumour effect in vivo, but any specific effects on the normal microvasculature and potential side-effects of this combination remain to be established. Methods: The effects of zoledronic acid and paclitaxel were investigated, alone and in combination, on human microvascular endothelial cells in vitro, using functional assays including proliferation, migration, tubule formation and apoptosis. The in vivo effect of the drugs on the normal microvasculature was determined using the dorsal microcirculation chamber model. Results/Conclusion: Zoledronic acid reduced human dermal microvascular endothelial cell (HuDMEC) proliferation, caused accumulation of cells in S phase, and inhibited migration, tube formation and Rap1a prenylation. Paclitaxel significantly inhibited tube formation and proliferation, and increased endothelial necrosis; the combination induced HuDMEC apoptosis and further enhanced the inhibition of tube formation and migration. The combination caused minimal effects on the normal microvasculature in vivo, suggesting that this potential therapeutic strategy is not associated with deleterious microvascular side-effects.

Rac1/Pak1/p38/MMP-2 Axis Regulates Angiogenesis in Ovarian Cancer

“…Detection of increased levels of unprenylated Rap1A is a surrogate measurement of NBP uptake by cells in vitro and of inhibition of prenylation (29–31). To confirm that the inhibition of angiogenesis occurs through the effect of ZA, we measured the levels of unprenylated Rap1A by western blot.…”

Bisphosphonates Inhibit Stellate Cell Activity and Enhance Antitumor Effects of Nanoparticle Albumin–Bound Paclitaxel in Pancreatic Ductal Adenocarcinoma

“…Detection of increased levels of unprenylated Rap1A is a common surrogate measurement of NBP uptake by cells in vitro and inhibition of the mevalonate pathway (25–27). The level of unprenylated Rap1A in PSCs increased as Pam concentration increased (by 137.8% at 0.1 μM to 297.5% at 10 μM compared with untreated cells) (Fig.…”

Selective Measurement and Manipulation of Adhesion Forces Between Cancer Cells and Bone Marrow Endothelial Cells Using Atomic Force Microscopy

“…The strong modulation of integrin CD49d may indicate a possible effect of zoledronic acid on cell anchorage [34]. Several studies have shown that zoledronic acid induces antiangiogenic responses, with reduced human dermal microvascular endothelial cell proliferation, accumulation of cells in S phase, and inhibition of migration, tube formation and Rap1a prenylation [35]. To determine the functional cellular responses to adhesion-blocking antibodies and zoledronic acid, a cell migration assay was performed, where the PC3 cells adhered to and migrated through a monolayer of BME cells.…”