title: 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.
authors.affiliation: Department of Biochemistry, College of Dentistry, Kyung Hee University, 130-701, Seoul, South Korea.
authors.forename: W
authors.initials: W
authors.lastname: Piao
authors.forename: J
authors.initials: J
authors.lastname: Yoo
authors.forename: D K
authors.initials: DK
authors.lastname: Lee
authors.forename: H J
authors.initials: HJ
authors.lastname: Hwang
authors.forename: J H
authors.initials: JH
authors.lastname: Kim
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis; D016203:CDC2 Protein Kinase / Q000378:metabolism; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D002455:Cell Division / Q000187:drug effects; D015536:Down-Regulation / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D016195:G2 Phase / Q000187:drug effects*; D018922:HL-60 Cells; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D015473:Leukemia, Promyelocytic, Acute; D008938:Mitosis / Q000187:drug effects*; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases; D011506:Proteins / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis; D013450:Sulfones / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D007093:Imidazoles; D011506:Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D013450:Sulfones; C499320:PARP1 protein, human; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases; D016203:CDC2 Protein Kinase; C505407:CASP3 protein, human; D053148:Caspase 3; D020169:Caspases; C404303:DW 2282