-We reported that (-)-xanthatin, a xanthanolide sesquiterpene lactone present in the Cocklebur plant, exhibited potent anti-proliferative effects on human breast cancer cells, in which GADD45γ, a novel tumor suppressor gene, was induced. Mechanistically, topoisomerase IIα (Topo IIα) inhibition by (-)-xanthatin was shown to be the upstream trigger that stimulated the expression of GADD45γ mRNA and concomitantly produced reactive oxygen species (ROS) to maintain this expression. Since the anticancer drug etoposide, a selective Topo IIα inhibitor, has also been shown to induce intracellular ROS, (-)-xanthatin may exert its anti-proliferative effects on cancer cells in a similar manner to those of etoposide. In the present study, to generalize its applicability to cancer therapy, we further investigated the biological activities of (-)-xanthatin by comparing its activities to those of the established anti-cancer drug etoposide. After the exposure of breast cancer cells to (-)-xanthatin or etoposide, a prolonged and marked up-regulation in the expression of c-fos, a proapoptotic molecule, was detected together with GADD45γ; and the expression of these molecules was stabilized by ROS and abrogated by the pretreatment with N-acetyl-L-cysteine (NAC), a potent ROS scavenger. (-)-Xanthatin in particular exhibited stronger antiproliferative potential than that of etoposide, which underlies the marked induction of c-fos/GADD45γ and ROS production.
-Sesquiterpene lactones exhibit toxicity in humans and animals by non-selectively interacting with cellular macromolecules. Among the sesquiterpene lactones identified to date, (-)-xanthatin, which was obtained in an extract from Xanthium strumarium (the Cocklebur plant), is reportedly less toxic to animals. Although we have shown that (-)-xanthatin has anti-proliferative effects, coupled with the induction of DNA damage-inducible GADD45γ, on highly aggressive human MDA-MB-231 breast cancer cells, the molecular mechanisms of anti-proliferative activity have not yet been elucidated in detail. Furthermore, evidence for the involvement of DNA damage is currently not sufficient. In the present study, we chemically synthesized pure (-)-xanthatin, and attempted to obtain more concrete evidence for DNA damage caused by (-)-xanthatin, which leads to cell death. The results obtained revealed the marked up-regulation of RhoB, which is up-regulated by DNA damage. We summarized the anti-proliferative effects of (-)-xanthatin in combination with our previous findings.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.