Combination of SK-7041, one of novel histone deacetylase inhibitors, and STI571-induced synergistic apoptosis in chronic myeloid leukemia.

Although ST1571 still plays a key role in the treatment of chronic myeloid leukemia, emergence of resistance to ST1571 is a major obstacle to successful outcome. Therefore, new agents that increase the sensitivity of chronic myeloid leukemia cells to ST1571 are urgently required. SK-7041 is a novel hybrid synthetic histone deacetylase inhibitor derived from the hydroxamic acid of trichostatin A and pyridyl ring of MS-275. Its cytotoxic effects were examined both as a single agent and in combination with ST1571 in acute and chronic myeloid leukemia. SK-7041 exhibited growth inhibition of leukemia cells by downregulation of CDK4, cyclin E and cyclin B1 expression, and by upregulation of p21(CIP1=WAF1) expression with subsequent activation of the mitochondria-mediated caspase pathway. SK-7041 showed synergism on growth inhibition, cell cycle arrest and induction of apoptosis in chronic myeloid leukemia (K562) when combined with STI571. The synergistic effect was mediated through the same mechanism as in SK-7041 alone, involving reduction of cyclin D1 and induction of p21(CIP1=WAF1). Taken together, our findings suggest that SK-7041 is active against leukemia and offers new prospects for overcoming STI571 resistance in chronic myeloid leukemia.