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HS-1200 Overcomes the Resistance Conferred by Bcl-2 in Human Leukemic U937 Cells  

Park, Jun-Young (Department of Oral Anatomy, School of Dentistry, Pusan National University)
Moon, Jeong-Bon (Department of Oral Anatomy, School of Dentistry, Pusan National University)
Kim, In-Ryoung (Department of Oral Anatomy, School of Dentistry, Pusan National University)
Kim, Gyoo-Cheon (Department of Oral Anatomy, School of Dentistry, Pusan National University)
Park, Bong-Soo (Department of Oral Anatomy, School of Dentistry, Pusan National University)
Kwak, Hyun-Ho (Department of Oral Anatomy, School of Dentistry, Pusan National University)
Publication Information
International Journal of Oral Biology / v.37, no.3, 2012 , pp. 91-102 More about this Journal
Abstract
Bcl-2 protects tumor cells from the apoptotic effects of various anti-neoplastic agents. Increased expression of Bcl-2 has been associated with a poor response to chemotherapy in various malignancies, including leukemia. Hence, bypassing the resistance conferred by anti-apoptotic factors such as Bcl-2 represents an attractive therapeutic strategy against cancer cells, including leukemic cells. This study was undertaken to examine whether the anticancer drug, cisplatin and the synthetic chenodeoxycholic acid (CDCA) derivative, HS-1200 show anti-tumor activity in U937 and U937/Bcl-2 cells. Viability assays revealed that HS-1200 overcomes the resistance conferred by Bcl-2 in human leukemic U937 cells. Various apoptosis assessment assays further demonstrated that HS-1200 overcomes the resistance conferred by Bcl-2 in human leukemic U937 cells by inducing apoptosis. In addition HS-1200, but not cisplatin, overcomes the anti-apoptotic effects of Bcl-2 in Bcl-2 over-expressing human leukemic cells (U937/Bcl-2 cells). Notably, we observed that the HS-1200-induced formation of mature promyelocytic leukemia (PML) nuclear bodies (NBs) correlates with a suppression of the anti-apoptotic effects of Bcl-2 in human leukemic cells over-expressing this protein (U937/Bcl-2 cells). Furthermore, HS-1200 was found to induce the association between PML and SUMO-1, Daxx, Sp100, p53 or CBP in the aggregated PML-NBs of U937/Bcl-2 cells. Thus, PML protein and the formation of mature PML-NBs could be considered as therapeutic targets that may help to bypass the resistance to apoptosis conferred by Bcl-2. Elucidating the exact mechanism by which PML regulates Bcl-2 will require further work.
Keywords
HS-1200; PML; bcl-2; apoptosis; U937 cells;
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