Combination of SK-7041, one of novel histone deacetylase inhibitors, and STI571-induced synergistic apoptosis in chronic myeloid leukemia.
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.
Kim
Byung-Su
BS
Department of Internal Medicine, Seoul National University College of Medicine, Seoul, South Korea.
Bae
Eunkyung
E
Kim
Young-Ju
YJ
Ahn
Kwang-Sung
KS
Park
Juwon
J
Rhee
Ji Young
JY
Lee
Young Yiul
YY
Kim
Youngsoo
Y
Lee
Dongsoon
D
Kim
Byoung Kook
BK
Yoon
Sung-Soo
SS
D000577:Amides / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D051017:Apoptosis Regulatory Proteins / Q000096:biosynthesis; D001549:Benzamides; D001713:Biphenyl Compounds / Q000494:pharmacology*; D002453:Cell Cycle / Q000187:drug effects; D018797:Cell Cycle Proteins / Q000096:biosynthesis; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D004357:Drug Synergism; D018922:HL-60 Cells; D056572:Histone Deacetylase Inhibitors; D006801:Humans; D000068877:Imatinib Mesylate; D020014:K562 Cells; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000473:pathology; D010879:Piperazines; D011743:Pyrimidines / Q000494:pharmacology*
D000577:Amides; D000970:Antineoplastic Agents; D051017:Apoptosis Regulatory Proteins; D001549:Benzamides; D001713:Biphenyl Compounds; D018797:Cell Cycle Proteins; D056572:Histone Deacetylase Inhibitors; D010879:Piperazines; D011743:Pyrimidines; C497103:SK-7041; D000068877:Imatinib Mesylate