An analysis of cytotoxic botanical formulations used in the traditional medicine of ancient Persia as abortifacients.

We report here an analysis of plants used by traditional healers of ancient Persia to induce abortions. Six herbal formulations that contain 39 different species from 21 plant families with their vernacular names, English names, amounts used, and their methods of preparation are reported. Our initial objective of this ethnobotanical analysis was to evaluate the validity and the efficacy of the plants used by (1) comparing other reported uses of these plants in traditional medicine, (2) investigating the medical and pharmacological literature on the medicinal properties of the plant species used, and (3) investigating the reported cytotoxic effects of compounds prevalent in these plants. Previous phytochemical analyses have shown that a number of plant species are rich in coumarin compounds that have potential antineoplastic or cytotoxic activities. Our results indicate a correlation between the reported use of these plants as abortifacients and their cytotoxic (antineoplastic) effects. In addition, we discuss the process in which this ethnobotanical investigation led to the discovery of dicoumarol (a coumarin anticoagulant) as a potential chemotherapeutic agent.

Dicoumarol: a unique microtubule stabilizing natural product that is synergistic with Taxol.

In studies on the antiproliferative actions of coumarin compounds, we discovered that dicoumarol (a coumarin anticoagulant; 3,3'-methylenebis[4-hydroxycoumarin]) inhibits the first cleavage of Strongylocentrotus purpuratus (sea urchin) embryos in a concentration-dependent manner with 50% inhibition occurring at a concentration of 10 microM. Because first cleavage in sea urchin embryos is highly selective for microtubule-targeted agents, we thought that the active compounds might inhibit cell division by interacting with tubulin or microtubules. We found that dicoumarol binds to bovine brain tubulin with a K(d) of 22 microM and that 0.1 microM dicoumarol strongly stabilizes the growing and shortening dynamics at the plus ends of the microtubules in vitro. Dicoumarol reduces the rate and extent of shortening, it increases the percentage of time the microtubules spend in an attenuated (paused) state, and it reduces the overall dynamicity of the microtubules. The antimitotic effects of the widely used cancer chemotherapeutic agent Taxol (paclitaxel) are also mediated by suppressing microtubule dynamics. We demonstrate that exposure to combinations of Taxol and dicoumarol results in a synergistic inhibition of cell division of sea urchin embryos. The results suggest that the antiproliferative mechanism of action of dicoumarol and possibly related pharmacophores may be mediated by tubulin binding and the stabilization of spindle microtubule dynamics. Because of its low toxicity and simple chemical structure, there is potential interest to explore combinations of antimitotic coumarins with other chemotherapeutic agents to improve efficacy and lower toxicity.