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

Byung Su Kim, Eunkyung Bae, Young Ju Kim, Kwang Sung Ahn, Juwon Park, Ji Young Rhee, Young Yiul Lee, Youngsoo Kim, Dongsoon Lee, Byoung Kook Kim, Sung Soo Yoon

Research output: Contribution to journalArticle

7 Scopus citations

Abstract

Although STI571 still plays a key role in the treatment of chronic myeloid leukemia, emergence of resistance to STI571 is a major obstacle to successful outcome. Therefore, new agents that increase the sensitivity of chronic myeloid leukemia cells to STI571 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 STI571 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 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. Taken together, our findings suggest that SK-7041 is active against leukemia and offers new prospects for overcoming STI571 resistance in chronic myeloid leukemia.

Original languageEnglish
Pages (from-to)641-647
Number of pages7
JournalAnti-cancer drugs
Volume18
Issue number6
DOIs
StatePublished - 1 Jul 2007

Keywords

  • Acute myeloid leukemia
  • Chronic myeloid leukemia
  • SK-7041 (glivec, histone deacetylase inhibitor)
  • STI571 (gleevec, imatinib)

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