Vascular disrupting activity and the mechanism of action of EHT 6706, a novel anticancer tubulin polymerization inhibitor

Abstract

Tumor blood vessels are an important emerging target for anticancer therapy. Here, we characterize the in vitro antiproliferative and antiangiogenic properties of the synthetic small molecule, 7-ethoxy-4-(3,4,5-trimethoxybenzyl)isoquinolin-8-amine dihydrochloride, EHT 6706, a novel microtubule-disrupting agent that targets the colchicine-binding site to inhibit tubulin polymerization. At low nM concentrations, EHT 6706 exhibits highly potent antiproliferative activity on more than 60 human tumor cell lines, even those described as being drug resistant. EHT 6706 also shows strong efficacy as a vascular-disrupting agent, since it prevents endothelial cell tube formation and disrupts pre-established vessels, changes the permeability of endothelial cell monolayers and inhibits endothelial cell migration. Genome-wide transcriptomic analysis of EHT 6706 effects on human endothelial cells shows that the antiangiogenic activity elicits gene deregulations of antiangiogenic pathways. These findings indicate that EHT 6706 is a promising tubulin-binding compound with potentially broad clinical antitumor efficacy.

Isoquinolinamine FX-9 Exhibits Anti-Mitotic Activity in Human and Canine Prostate Carcinoma Cell Lines

“…Given the reduced effect of FX-9 on slower proliferating benign cells, as well as the clear impact on cell cycle (induction of apoptosis during proliferation, G2/M phase enrichment and formation of multinucleated cells), FX-9 induces its anti-cancer effects in an anti-mitotic manner. Induced G2/M-phase cell cycle arrest has been shown for some isoquinolinamine agents already [24,25,26] partly due to tubulin polymerization inhibition. Prolonged mitotic arrest will eventually lead to cell death by apoptosis as detected for the PCa cell lines exposed to FX-9.…”

“…Amino-substituted isoquinoline structures are considered as tracers in positron emission tomography (PET) imaging [17,18,19] but also show a broader range of inhibitory [20,21,22] and cytotoxic effects e.g., activity against fungi [21], malaria [23], and cancer [22,24,25,26]. Recently, our group showed that novel synthesized isoquinolinamine FX-9 inhibits proliferation and induces apoptosis in human B- and T-acute lymphoblastic leukemia (ALL) cell lines, but displays no hemolysis on erythrocytes or cytotoxicity against non-neoplastic leukocytes.…”

Desacetylvinblastine Monohydrazide Disrupts Tumor Vessels by Promoting VE-cadherin Internalization

“…Endothelial cell hyperpermeability is a major reason for VDA-induced tumor vascular disruption 20 . Vascular endothelial cadherin (VE-cadherin) is the endothelial-specific transmembrane component that localizes exclusively at endothelial cell-cell contacts; it maintains endothelial permeability and vessel integrity by homophilic interactions and association with catenins, including β-catenin and p120-catenin 21 , 22 .…”