Blocking Blood Flow to Solid Tumors by Destabilizing Tubulin: An Approach to Targeting Tumor Growth

Abstract

The unique characteristics of the tumor vasculature offer the possibility to selectively target tumor growth and vascularization using tubulin-destabilizing agents. Evidence accumulated with combretastatin A-4 (CA-4) and its prodrug CA-4P support the therapeutic value of compounds sharing this mechanism of action. However, the chemical instability and poor solubility of CA-4 demand alternative compounds that are able to surmount these limitations. This Perspective illustrates the different classes of compounds that behave similar to CA-4, analyzes their binding mode to αβ-tubulin according to recently available structural complexes, and includes described approaches to improve their delivery. In addition, dissecting the mechanism of action of CA-4 and analogues allows a closer insight into the advantages and drawbacks associated with these tubulin-destabilizing agents that behave as vascular disrupting agents (VDAs).

Synthesis of a 3′-C-ethynyl-β-d-ribofuranose purine nucleoside library: Discovery of C7-deazapurine analogs as potent antiproliferative nucleosides

“…Agents capable of modifying the tumor vasculature, either by antiangiogenic or vascular-disrupting action, are of interest for antitumor therapies both as single agents and in combination with other chemotherapeutic drugs. Disruption of vascular networks in solid tumors may induce their collapse by deprivation of oxygen and other nutrients [45]. Nucleoside analogs 31e34, 37 were found to potently inhibit the proliferation of the three endothelial cell types studied, with the halogenated derivatives 32 (Cl) and 33 (Br) being most potent.…”

Conformational mimetics of the α-methyl chalcone TUB091 binding tubulin: Design, synthesis and antiproliferative activity

“…The low solubility issue has been addressed through the synthesis of prodrugs, of which the phosphate of CA-4 (fosbretabulin, 4) [8] or the diphosphate of CA-1 (OXi4503, 5) [9] are being tested in clinical trials. Concerning the stability of the cis stilbene, many efforts have been performed to fix the cis conformation by incorporation of the stilbene into a restricted bridge or by replacing it by other linkers, as recently reviewed [10][11][12][13].…”

Starvation tactics using natural compounds for advanced cancers: pharmacodynamics, clinical efficacy, and predictive biomarkers

“…Of note, blood vessels of tumors differ from normal resting blood vessels; this difference makes tumor blood vessels a reliable target for tumor-directed treatment. Classically, vascular-targeted therapeutic agents may act by neutralizing the angiogenic proteins, inhibiting their synthesis by cancer cells, directly inducing endothelial cell (EC) apoptosis, inhibiting endothelial receptors of angiogenic proteins [11,12], or by disrupting tubulin network of the established tumor vasculature REVIEW Starvation tactics using natural compounds for advanced cancers: pharmacodynamics, clinical efficacy, and predictive biomarkers and therefore tumor blood flow interruption [13][14][15][16][17]. The nutritional supply of tumor tissues is under the regulation of various cytokines that (1) increases the permeability and the widening of tumor blood vessels, (2) stimulates proteolytic enzymes and cellular infiltration, (3) rebuilds blood vessels, and (4) protects ECs from apoptosis.…”