Imidazoacridinone C-1311 (Symadex ^TM), which demonstrated potent antitumor activity against several experimental tumors, has recently entered phase II clinical trials. C-1311 has previously been shown to display DNA-binding properties and to inhibit activity of topoisomerase II. One of the early biological effects induced by pharmacologically relevant doses of C-1311 was arrest in the G2M phase of the cell cycle and subsequent apoptosis.

The aim of this study was to examine the influence of C-1311 on the cell cycle progression as well as the ability of this drug to induce apoptosis of human breast carcinoma MCF7 cells.

C-1311 inhibited MCF-7 cells proliferation in a concentration dependent manner. The concentration which caused 80% growth inhibition (EC₈₀ = 1 ± 0.07 μM) was estimated by cell counting using Coulter Counter.

C-1311 at EC₈₀ concentration induced transient G2M arrest starting from 48 h (~53%) as was analyzed by flow cytometry. However, during prolonged incubation with the drug, the decrease in percentage of cells arrested in G2M phase of the cell cycle was observed. Moreover, progressive disappearance of G2M arrested cells was accompanied by an appearance of cells with sub-G1 levels of DNA (7% after 48 h and 26% after 120 h), what suggest induction of apoptosis of MCF-7 cells.

This was additionally proved by morphological survey of cells (stained with DAPI). After 24 h of drug treatment in cells was observed: larger nuclei than control, probably due to accumulation in the G2M phase, condensed chromatin and apoptotic body-like structures. Enlarged cells with multiple micronuclei, typical for mitotic catastrophe, were also appeared. Prolonged incubation with drug (48 h and longer) resulted in further increase in percentage of apoptotic and multinucleated cells.

Disruption of mitochondrial transmembrane potential ∆ Ψ_m in C-1311 treated MCF-7 cells (measured by flow cytometry using JC-1) was observed after 24 h of incubation and was intensified after 48 - 120 h of incubation with the drug. This observation additionally confirmed induction of apoptosis of MCF-7 cells by C-1311, in a time dependent manner.

In summary our data indicate, that C-1311 at biologically relevant concentration, induced cell cycle arrest in the G2M phase of human breast carcinoma MCF7 cells. This cell cycle effect was followed by apoptosis, but only in part of MCF7 cells.

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