Taccalonolide Microtubule Stabilizers.

Microtubule stabilizers are a mainstay in the treatment of many solid cancers and continue to find utility in combination therapy with molecularly targeted anticancer agents and immunotherapeutics. However, innate and acquired resistance to microtubule stabilizers can limit their clinical efficacy. The taccalonolides are a unique class of microtubule stabilizers isolated from plants of Tacca that circumvent clinically relevant mechanisms of drug resistance. Although initial reports suggested that the microtubule-stabilizing activity of the taccalonolides was independent of direct tubulin binding, additional studies have identified that potent C-22, C-23 epoxidized taccalonolides covalently bind the Aspartate 226 residue of ß-tubulin and that this interaction is critical for their microtubule-stabilizing activity. The taccalonolides have distinct properties as compared to other microtubule stabilizers with regard to their biochemical effects on tubulin structure and dynamics that promote distinct cellular phenotypes. Some taccalonolides have demonstrated in vivo antitumor efficacy in drug-resistant tumor models with exquisite potency and long-lasting antitumor efficacy as a result of their irreversible target engagement. The recent identification of a site on the taccalonolide scaffold that is amenable to modification has provided evidence of the specificity of the taccalonolide-tubulin interaction. This also affords an opportunity to further optimize the targeted delivery of the taccalonolides to further improve their anticancer efficacy and potential for clinical development.

Extreme reproduction and survival of a true cliffhanger: the endangered Plant Borderea chouardii (Dioscoreaceae).

Cliff sides are extreme habitats, often sheltering a rich and unique flora. One example is the dioecious herb Borderea chouardii (Dioscoreaceae), which is a Tertiary, tropical relict, occurring only on two adjacent vertical cliffs in the world. We studied its reproductive biology, which in some aspects is extreme, especially the unusual double mutualistic role of ants as both pollinators and dispersers. We made a 2-year pollination census and four years of seed-dispersal experiments, recording flower visitors and dispersal rates. Fruit and seed set, self-sowing of seeds, seedling recruitment, and fate of seedlings from seeds sowed by different agents were scored over a period of 17 years. The ants Lasius grandis and L. cinereus were the main pollinators, whereas another ant Pheidole pallidula dispersed seeds. Thus ants functioned as double mutualists. Two thirds of all new seedlings came from self-sown seeds, and 1/3 was dispersed by ants, which gathered the seeds with their oil-rich elaiosome. Gravity played a minor role to dispersal. Both ant dispersal and self-sowing resulted in the same survival rate of seedlings. A double mutualism is a risky reproductive strategy, but B. chouardii buffers that by an unusual long-term demographic stability (some individuals exceed 300 years in lifespan) and its presence in a climatically very stable habitat, inaccessible to large herbivores. Such a combination of traits and habitat properties may explain the persistence of this relict species.

Age and sex-related changes in cytokinins, auxins and abscisic acid in a centenarian relict herbaceous perennial.

It is still an unsolved question of fundamental biology if, and how, perennial plants senesce. Here, age- and sex-related changes in phytohormones were tested in Borderea pyrenaica, a small dioecious geophyte relict of the Tertiary with one of the longest lifespan ever recorded for any non-clonal herb (more than 300 years). Biomass allocation, together with levels of cytokinins, auxins and absicisic acid, and other indicators of leaf physiology (chlorophylls, lipid peroxidation and F (v)/F (m) ratio) were measured in juvenile and mature plants, including both males and females of three age classes (up to 50 years, 50-100 years, and over 100 years). Plants maintained intact capacity of their vegetative growth and reproductive potential. Cytokinin levels decreased with age, but only in females. Such sex-related differences, however, were not associated with symptoms of physiological deterioration in leaves, but with an increased reproductive effort in females. It is concluded that B. pyrenaica does not show clear signs of senescence at the organism level. Altered cytokinin levels in females were associated with their reproductive effort, rather than to a degenerative process. The alternate use of five meristematic points in the tuber could explain the extraordinary longevity of this species.