Mitotic slippage in non-cancer cells induced by a microtubule disruptor, disorazole C1

In non-cancer cells, disorazole C1 induced a prolonged mitotic arrest, followed by mitotic slippage, as confirmed by live cell imaging and cell cycle analysis. This mitotic slippage was associated with cyclin B degradation, but did not require p53. Four assays for apoptosis, including western blotting for poly(ADP-ribose) polymerase cleavage, microscopic analyses for cytochrome C release and annexin V staining, and gel electrophoresis examination for DNA laddering, were conducted and demonstrated little induction of apoptosis in non-cancer cells treated with disorazole C1. On the contrary, we observed an activated apoptotic pathway in cancer cells, suggesting that normal and malignant cells respond differently to disorazole C1.Our studies demonstrate that non-cancer cells undergo mitotic slippage in a cyclin B-dependent and p53-independent manner after prolonged mitotic arrest caused by disorazole C1. In contrast, cancer cells induce the apoptotic pathway after disorazole C1 treatment, indicating a possibly significant therapeutic window for this compound.Microtubules are dynamic polymers that facilitate transport and movement within the cell [1]. Microtubule dynamics are a critical aspect of mitosis, ensuring accurate chromosome capture and segregation [1,2]. Factors that interfere with microtubule attachment keep the mitotic spindle checkpoint unsatisfied, thus causing mitotic arrest and inhibition of cell proliferation [3].Microtubule dynamics can be modified by two groups of chemical inhibitors. The first group, represented by taxanes, stabilizes microtubules and is clinically used to treat breast, lung, bladder and head and neck cancers [4]. The second group of modifiers include vinblastine, vincristine, and vinorelbine, disrupt microtubules and are used in the treatment of leukemia, lymphoma, small cell lung and breast cancer, and other malignancies [5]. Although these chemotherapeutic drugs are efficacious, new drug development is still needed due to intrinsi