Induction of G2/M phase arrest and apoptosis by a novel indoloquinoline derivative, IQDMA, in K562 cells

The indoloquinoline, IQDMA (N'-(11H-indolo[3,2-c]quinolin-6-yl)-N,N-dimethylethane-1, 2-diamine), was identified as a novel antineoplastic agent with broad spectrum of antitumor activities against several human cancer cells. IQDMA-induced G2/M arrest was accompanied by up-regulation of the cyclin-dependent kinase inhibitors (CDKIs), p21 and p27, and down-regulation of Cdk1 and Cdk2. IQDMA had no effect on the levels of cyclin A, cyclin B1, cyclin D3, or Cdc25C. IQDMA also increased apoptosis, as characterized by apoptotic body formation, increase of the sub G, population and poly (ADP-ribose) polymerase (PARP) cleavage. Further mechanistic analysis demonstrated that IQDMA upregulated FasL protein expression, and kinetic studies showed the sequential activation of caspases-8, -3, and -9. Both caspase-8 and caspase-3 inhibitors, but not a caspase-9-specific inhibitor, suppressed IQDMA-induced cell death. These molecular alterations provide an insight into IQDMA-caused growth inhibition, G2/M arrest, and apoptotic death of K562 cells.