DYZ-2-90, a Novel Neo-tanshinlactone Ring-Opened Compound, Induces ERK-Mediated Mitotic Arrest and Subsequent Apoptosis by Activating JNK in Human Colorectal Cancer Cells

Abstract

Over the past several decades, there has been a considerable and still growing interest in discovering natural products with anticancer potential from traditional Chinese medicine and increasing their anticancer selectivity by chemical modification. In addition, total synthesis of active compounds from natural products can overcome problems related to poor resource availability. DYZ-2-90 is a novel ring-opened compound modified from neo-tanshinlactone, which is isolated from Chinese medicinal herb tanshen. Both in vitro and in vivo tubulin polymerization assays showed that DYZ-2-90 directly bound to microtubules and rapidly induced tubulin depolymerization, inducing ERK-mediated mitotic arrest and subsequent apoptosis by JNK activation in cancer cells, respectively. These results suggest that the fate of cells that undergo mitotic arrest is dictated by two competing networks activated by DYZ-2-90: the cytoprotective ERK pathway and the stress-related JNK pathway. DYZ-2-90 is therefore a novel microtubule-destabilizing agent and a new drug candidate for cancer therapy. This paper provides a new insight into the model of mitotic cell death, which was proposed in order to elucidate how cancer cells respond to microtubule-interfering agents and prolonged cell cycle delay.