MCS-5A, an analog of sangivamycin, selectively inhibits the cyclin-dependent kinases CDK1 and 4 in HL-60 cells in vitro (IC(50): 9.6 and 8.8 1V, respectively), while weakly inhibiting other housekeeping protein kinases. MCS-5A effectively induces HL-60 cell cycle arrest at the G(1) and G(2)/M phases through direct inhibition of CDK1 and 4 activity. In addition, elevated expression of p16(INK4a) and a reduction in the level of hyperphosphorylated pRb showed that 3 1V MCS-5A also induces p16(INK4a)-mediated cell cycle arrest at the G(1) phase. Furthermore, apoptotic induction in MCS-5A-treated HL-60 cells is associated with the release of cytochrome c from mitochondria, which, in turn, results in the activation of procaspase-8, -9 and -3, and the cleavage of poly(ADP-ribose) polymerase (PARP). In addition, the involvement of p16(INK4a) in this apoptotic induction was demonstrated using A549 cells with a homozygous deletion of p16(INK4a). Based on these results, we conclude that MCS-5A is a candidate therapeutic agent for the treatment of human promyelocytic leukemia via the up-regulation of p16(INK4a).
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