Antiangiogenic activity of paclitaxel is associated with its cytostatic effect, mediated by the initiation but not completion of a mitochondrial apoptotic signaling pathway

Abstract

Angiogenesis is a critical event in tumor growth and metastasis, which can be inhibited by conventional anticancer drugs such as the microtubule-damaging agent paclitaxel (Taxol). In this study, we investigate the mechanism of action of paclitaxel on human endothelial cells. We characterize two distinct effects of paclitaxel on human umbilical vein endothelial cell and human microvascular endothelial cell-1 proliferation according to drug concentration: a cytostatic effect at low concentrations and a cytotoxic effect at concentrations 10 nmol/L. The cytotoxic effect involves signaling pathways similar to those described in tumor cells (i.e., microtubule network disturbance, G2-M arrest, increase in Bax/Bcl-2 ratio, and mitochondria permeabilization) that result in apoptosis. In sharp contrast, the cytostatic effect involves an inhibition of endothelial cell proliferation without apoptosis induction and without any structural modification of the microtubule network. This cytostatic effect is due to a slowing of the cell cycle rather than to an arrest in a specific phase of the cell cycle. In addition, paclitaxel, at cytostatic concentrations, early initiates an apoptotic signaling pathway associated with increases in the mitochondrial reducing potential, mitochondrial membrane potential, p53 expression, and Bax/Bcl-2 ratio. However, this apoptotic pathway is stopped upstream of mitochondria permeabilization and it does not lead to endothelial cell death. Finally, we found that paclitaxel inhibits endothelial cell morphogenesis on Matrigel at all tested concentrations. In conclusion, we describe the mechanism of action of low concentrations of paclitaxel related to the antiangiogenic properties of this drug.

Endothelial‐Smooth Muscle Cell Interactions in a Shear‐Exposed Intimal Hyperplasia on‐a‐Dish Model to Evaluate Therapeutic Strategies

“…In vitro, paclitaxel has been shown to have a toxic effect on s-SMCs and ECs above 0.01 × 10 −6 m and a cytostatic effect below. [78,79] In agreement with these results, on both s-SMC and EC monocultures under static conditions, 0.01 × 10 −6 m paclitaxel only exerted a cytostatic effect, as seen by the constant WST-assay absorbance overtime compared to the increasing values in controls (Figure 6A,B). Also under shear, 0.01 × 10 −6 m of paclitaxel had no cytotoxic effect in both s-SMCs and ECs, but reduced s-SMC growth and EC alignment to shear compared to controls (Figure 6C,D).…”

Enhanced Antiglioblastoma Efficacy of Neovasculature and Glioma Cells Dual Targeted Nanoparticles

“…Paclitaxel (PTX) is a widely used chemotherapy drug against various tumors including breast cancers, ovaries tumors, lung cancers, head, and neck tumors. − However, the clinical use of PTX is greatly hampered by the hydrophobicity and serious side effects . Exception of direct toxicity to tumor cells, PTX exhibits inhibition on proliferation, migration, and tube formation of endothelial cell at a very low concentration, which is presenting an attractive antiangiogenic activity. − In this study, we developed a PTX loaded synergetic targeted polymer nanoparticles based on Pep-1 and CGKRK modification (PC-NP-PTX) for glioma treatment, which aimed at improving the antiglioma efficacy via antiangiogenesis and cancerous cytotoxicity (Figure ). Cellular uptake of the functionalized nanoparticles and antiproliferation assay were investigated in both C6 and HUVEC cells.…”

Antiangiogenic Antitumor Activity of HPMA Copolymer–Paclitaxel–Alendronate Conjugate on Breast Cancer Bone Metastasis Mouse Model

“…Breast cancer almost invariably metastasizes to bones in patients with advanced disease. , These bone metastases are responsible for much of the disabling morbidity (pain, pathological fractures, hypercalcemia) and mortality . The taxane paclitaxel (PTX), which interferes with microtubule breakdown during cell division, is a known potent cytotoxic agent approved as first line of therapy for metastatic breast cancer. − Also, it has become evident that ultralow (e.g., picomolar) concentrations of PTX can selectively inhibit endothelial functions relevant to angiogenesis. , Despite the strong anticancer and antiangiogenic activity, PTX exhibits serious dose-limiting toxicities due to nonspecific biodistribution of the drug in both tumors and normal tissues. In addition, PTX is water-insoluble and, therefore, it is formulated in Cremophor EL vehicle, which causes severe allergic, hypersensitivity, and anaphylactic reactions .…”

“…3À7 Also, it has become evident that ultralow (e.g., picomolar) concentrations of PTX can selectively inhibit endothelial functions relevant to angiogenesis. 8,9 Despite the strong anticancer and antiangiogenic activity, PTX exhibits serious dose-limiting toxicities due to nonspecific biodistribution of the drug in both tumors and normal tissues. In addition, PTX is water-insoluble and, therefore, it is formulated in Cremophor EL vehicle, which causes severe allergic, hypersensitivity, and anaphylactic reactions.…”