Probing the role of the potent microtubule disrupting agent disorazole C1 in premature cellular senescence induction

Abstract

Cellular senescence is a permanent state of cell cycle arrest that prevents cell proliferation but allows the cells to be metabolically active. Premature cellular senescence is stimulated by a variety of extracellular and intracellular stimuli including oxidative damage, supraphysiological mitogenic signaling, transforming growth factor‐β, retinoids, oncogenes, DNA damage and some cancer chemotherapeutic agents. Disorazoles are macrocyclic polyketides isolated from the fermentation broth of the myxobacterium Sorangium cellulosum that are potent inhibitors of tubulin polymerization. We synthesized disorazole C1 and found it inhibited in vitro tubulin polymerization and competed with vinblastine and dolastatin 10 for binding to purified tubulin. Treatment with disorazole C1 caused profound inhibition of cell proliferation in a wide variety of cancer cell lines. In cells surviving 7 days of treatment, disorazole C1 induced a senescent phenotype at concentrations equal to or below the IC50 for growth inhibition. Additionally, we observed that a variety of other inhibitors of tubulin polymerization also induced a senescent phenotype indicating that, like other mechanisms of cellular stress, microtubule disruption can induce premature cellular senescence. This research was funded in part by USPH grant CA78039.