The Bat Flower: A Source of Microtubule-Destabilizing and -Stabilizing Compounds with Synergistic Antiproliferative Actions

Abstract

The biosynthesis of secondary metabolites provides higher plants with mechanisms of defense against microbes, insects, and herbivores. One common cellular target of these molecules is the highly conserved microtubule cytoskeleton, and microtubule-targeting compounds with insecticidal, antifungal, nematicidal, and anticancer activities have been identified from plants. A new retro-dihydrochalcone, taccabulin A, with microtubule-destabilizing activity has been identified from the roots and rhizomes of <i>Tacca</i> species. This finding is notable because the microtubule-stabilizing taccalonolides are also isolated from these sources. This is the first report of an organism producing compounds with both microtubule-stabilizing and -destabilizing activities. A two-step chemical synthesis of taccabulin A was performed. Mechanistic studies showed that taccabulin A binds within the colchicine site on tubulin and has synergistic antiproliferative effects against cancer cells when combined with a taccalonolide, which binds to a different site on tubulin. Taccabulin A is effective in cells that are resistant to many other plant-derived compounds. The discovery of a natural source that contains both microtubule-stabilizing and -destabilizing small molecules is unprecedented and suggests that the synergistic action of these compounds was exploited by nature long before it was discovered in the laboratory