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KMID : 0848120120370030091
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International Journal of Oral Biology
2012 Volume.37 No. 3 p.91 ~ p.102
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HS-1200 Overcomes the Resistance Conferred by Bcl-2 in Human Leukemic U937 Cells
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Kwak Hyun-Ho
Park Jun-Young
Moon Jeong-Bon
Kim In-Ryoung
Kim Gyoo-Cheon
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Abstract
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Bcl-2 protects tumor cells from the apoptotic effects ofvarious anti-neoplastic agents. Increased expression ofBcl-2 has been associated with a poor response to chemotherapyin various malignancies, including leukemia.Hence, bypassing the resistance conferred by anti-apoptoticfactors such as Bcl-2 represents an attractive therapeuticstrategy against cancer cells, including leukemic cells.This study was undertaken to examine whether the anticancerdrug, cisplatin and the synthetic chenodeoxycholicacid (CDCA) derivative, HS-1200 show anti-tumor activityin U937 and U937/Bcl-2 cells. Viability assays revealedthat HS-1200 overcomes the resistance conferred by Bcl-2in human leukemic U937 cells. Various apoptosis assessmentassays further demonstrated that HS-1200 overcomesthe resistance conferred by Bcl-2 in human leukemic U937cells by inducing apoptosis. In addition HS-1200, but notcisplatin, overcomes the anti-apoptotic effects of Bcl-2 inBcl-2 over-expressing human leukemic cells (U937/Bcl-2cells). Notably, we observed that the HS-1200-induced formationof mature promyelocytic leukemia (PML) nuclear bodies(NBs) correlates with a suppression of the anti-apoptoticeffects of Bcl-2 in human leukemic cells over-expressingthis protein (U937/Bcl-2 cells). Furthermore, HS-1200 wasfound to induce the association between PML and SUMO-1,Daxx, Sp100, p53 or CBP in the aggregated PML-NBs ofU937/Bcl-2 cells. Thus, PML protein and the formation of mature PML-NBs could be considered as therapeutictargets that may help to bypass the resistance to apoptosisconferred by Bcl-2. Elucidating the exact mechanism bywhich PML regulates Bcl-2 will require further work.
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KEYWORD
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HS-1200, PML, bcl-2, apoptosis, U937 cells
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