Disorazol A 1, a highly effective antimitotic agent acting on tubulin polymerization and inducing apoptosis in mammalian cells

Abstract

Disorazol A 1, a macrocyclic polyketide compound that is produced by the myxobacterium Sorangium cellulosum showed a remarkably high cytostatic activity. It inhibited the proliferation of different cancer cell lines including a multidrug-resistant KB line at low picomolar levels. In presence of disorazol A 1, the nuclei of the cells increased in size and the cells often became multinucleate. Low concentrations of disorazol (<100 pM) induced an apoptotic process, characterized by enhanced capase-3 activity and DNA laddering, and abnormal, multipolar mitotic spindles. Low concentrations also induced an accumulation of p53 protein in the nucleus. At higher concentrations, we observed an accumulation of the cells in the G 2/M-phase of the cell cycle, and a depletion of microtubules. In vitro, disorazol A 1 inhibited the polymerization of tubulin in a concentration-dependent manner and independently of microtubule-associated proteins. Correspondingly it induced a complete depolymerization of microtubules prepared in vitro. Formation of defined degradation structures was not observed. Disorazol is a novel, highly effective antimitotic agent. Efforts are going on to develop it as an anticancer drug.