Antitumour imidazoacridone C-1311 induces cell death by mitotic catastrophe in human colon carcinoma cells

In this study, we investigated the cell death process induced by imidazoacridone C-1311 (Symadex(TM)) in HT-29 human colon carcinoma cells which have been shown to be preferentially sensitive to this compound in experimental tumour models both in vitro and in nude mice. Compound C-1311 at the EC99 dose delayed progression of cells through the S phase which was followed by G2 arrest. At 4896 h after drug exposure, an increasing fraction of cells rounded up and detached from the substratum which suggested the induction of cell death. This was confirmed by the induction of DNA fragmentation as revealed by pulse field electrophoresis and DNA strand breaks by the TUNEL assay. The dying cells had also mitotic features which were evidenced by various biochemical and morphological criteria such as activation of Cdk1 kinase, presence of the mitotic epitope MPM-2 and condensation of chromatin into mitotic chromosomes in drug-treated cells. These results show that C-1311 does not induce rapid apoptosis in HT-29 cells, instead drug exposure leads to prolonged G2 arrest followed by G2 to M transit and cell death during mitosis in the process of mitotic catastrophe. (C) 2004 Elsevier Inc. All rights reserved.