Combretastatin analogues in cancer biology: A prospective view

The stilbenoid combretastatin and its derivatives are potent inhibitors of angiogenesis and cell proliferation and induce apoptosis. They disrupt cytoskeletal dynamics and modulate cell morphology, motility, and invasion. Hence they have been viewed as potential as anticancer agents. The impediments of poor solubility and bioavailability and the spontaneous geometric isomerisation of combretastatin into an inactive form have led to intensive efforts towards evolving novel analogues to provide more efficacious biological outcome. Importantly, isomerically stable and biologically active cis-restricted analogues have been synthesised and tested. However, very few analogues have been tested in preclinical models to assess their effects on processes relevant to cancer development and progression. Hence the accent here is on the signalling systems operated by the new derivatives and their biological effects with reference to cancer progression. Combretastatins modulate an extensive network of signalling emphasising their varied versatility. Harnessing these systems and accentuating or counteracting aberrant signalling could open potential avenues of approach to the designing of novel derivatives with enhanced performance. The import of mammalian target of rapamycin pathway, which co-ordinates growth factor receptor signalling, epithelial-mesenchymal transition activation and angiogenic signalling, is emphasised. It may be viewed as a prime target for allosteric inhibition in combination with combretastatin analogues to ascertain their potential in cancer control.