The Protein Kinase C Inhibitor Ilmofosine (BM 41 440) Arrests Cells in G2 Phase and Suppresses CDC2 Kinase Activation Through a Mechanism Different from That of DNA Damaging Agents

The thioether phospholipid derivative ilmofosine (BM41440), a selective inhibitor of protein kinase C, is a new anticancer drug presently undergoing Phase II clinical trials. We have examined the influence of the compound on cell cycle progression. Ilmofosine was found to induce a dose-dependent accumulation of CA46 cells in G2-phase of the cell cycle. G2-arrest correlated with suppression of cdc2 kinase activation. Ilmofosine did not affect cdc2 kinase activity in vitro, consistent with an indirect locus of action. Ilmofosine treated CA46 cells failed to accumulate hyperphosphorylated-cdc2/cyclin B1 complexes that are observed when G2-arrest is induced by either nitrogen mustard or ionizing radiation. Indeed, cdc2 became dephosphorylated and cyclin B1 protein levels decreased as ilmofosine treated cells became arrested in G2. Our findings suggest that ilmofosine down-regulates cdc2 kinase activation through a mechanism that affects the formation of cdc2/cyclin B1 complexes.