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Induction of G(2)/M phase arrest and apoptosis by a new synthetic anti-cancer agent, DW2282, in promyelocytic leukemia (HL-60) cells.

Abstract：

:We studied the effect of DW2282-,[(S)-(+)-4-phenyl-1-[N-(4-aminobenzoyl)-indoline-5-sulfonyl-4,5-dihydro-2-imidazolone].hydrochloride], a newly developed anti-cancer agent, on cell proliferation, cell cycle progression, and induction of apoptosis in human promyelocytic leukemia (HL-60) cells. DW2282, a diarylsulfonylurea compound, was cytotoxic to HL-60 cells, with an IC(50) of 1.0 microg/mL. Treatment with DW2282 fragmented DNA in a concentration- and time-dependent manner, suggesting that these cells underwent apoptosis. Flow cytometric analysis further confirmed that DW2282-treated HL-60 cells were hypodiploid, in terms of DNA content, and were arrested at the G(2)/M phase. The cell cycle arrest was reversible upon the removal of DW2282. HL-60 cells also underwent distinct morphological changes in response to DW2282 treatment, including the appearance of elongated cells with conical tails and other apoptotic characteristics. G(2)/M phase cell cycle arrest was accompanied by a decrease in the levels of cdc2, a protein that plays a critical role for progression through the G(2)/M phase. Treatment of HL-60 cells with DW2282 was also associated with decreased levels of the anti-apoptotic protein Bcl-2, activation of caspase-3, and proteolytic cleavage of poly(ADP-ribose) polymerase. Taken together, these results demonstrate that DW2282 dramatically suppressed HL-60 cell growth by inducing apoptosis after G(2)/M phase arrest. These findings are consistent with the possibility that G(2)/M phase arrest was mediated by the down-regulation of cdc2 levels in HL-60 cells. The data also suggest that DW2282 triggered apoptosis by decreasing Bcl-2 levels and activating caspase-3 protease. These results provide important new information towards understanding the mechanisms by which DW2282 and other diarylsulfonylureas mediate their therapeutic effects.

journal_name

Biochem Pharmacol

journal_title

Biochemical pharmacology

authors

Piao W,Yoo J,Lee DK,Hwang HJ,Kim JH

doi

10.1016/s0006-2952(01)00796-1

subject

Has Abstract

pub_date

2001-12-01 00:00:00

pages

1439-47

issue

eissn

0006-2952

issn

1873-2968

pii

S0006295201007961

journal_volume

pub_type

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Induction of G(2)/M phase arrest and apoptosis by a new synthetic anti-cancer agent, DW2282, in promyelocytic leukemia (HL-60) cells.