Abstract
Microtubules are dynamic polymers that occur in eukaryotic cells and play important roles in cell division, motility, transport and signaling. They form during the process of polymerization of α- and β-tubulin dimers. Tubulin is a significant and heavily researched molecular target for anticancer drugs. Combretastatins are natural cis-stilbenes that exhibit cytotoxic properties in cultured cancer cells in vitro. Combretastatin A-4 (3′-hydroxy-3,4,4′, 5-tetramethoxy-cis-stilbene; CA-4) is a potent cytotoxic cis-stilbene that binds to β-tubulin at the colchicine-binding site and inhibits tubulin polymerization. The prodrug CA-4 phosphate is currently in clinical trials as a chemotherapeutic agent for cancer treatment. Numerous series of stilbene analogs have been studied in search of potent cytotoxic agents with the requisite tubulin-interactive properties. Microtubule-interfering agents include numerous CA-4 and transresveratrol analogs and other synthetic stilbene derivatives. Importantly, these agents are active in both tumor cells and immature endothelial cells of tumor blood vessels, where they inhibit the process of angiogenesis. Recently, computer-aided virtual screening was used to select potent tubulin-interactive compounds. This review covers the role of stilbene derivatives as a class of antitumor agents that act by targeting microtubule assembly dynamics. Additionally, we present the results of molecular modeling of their binding to specific sites on the α- and β-tubulin heterodimer. This has enabled the elucidation of the mechanism of stilbene cytotoxicity and is useful in the design of novel agents with improved anti-mitotic activity. Tubulin-interactive agents are believed to have the potential to play a significant role in the fight against cancer.
Highlights
The high incidence of cancer and the high cost of its treatment are important factors driving the search for new and effective chemotherapeutic substances with multi-target activity and no toxicity to normal cells
This review focuses on the anti-carcinogenic properties of natural and modified stilbenes with respect to their interaction with the cellular protein tubulin
The combination of the trans-isomer with combretastatin A-4 (CA-4) increased the anti-tumor efficacy of the latter agent to near that of cis-combretastatin A-1 diphosphate (CA-1P). These findings indicate that while the predominant in vivo effect of CA-1P is due to microtubule disruption and vascular shutdown, the formation of oxiquinones – toxic free radicals – could yield additional cytotoxic effects in vivo
Summary
The high incidence of cancer and the high cost of its treatment are important factors driving the search for new and effective chemotherapeutic substances with multi-target activity and no toxicity to normal cells. Studies on their interaction with tubulin-binding sites have provided information on the mechanism of anti-mitotic activity of potential drugs used for cancer treatment and allowed scientists to develop new and efficient chemotherapeutics. The interest in stilbenes as tubulin-interactive agents was inspired by the work of Pettit, who first isolated combretastatins and determined their anti-mitotic activity in the 1980s [2].
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