SAHA treatment overcomes the anti-apoptotic effects of Bcl-2 and is associated with the formation of mature PML nuclear bodies in human leukemic U937 cells |
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Authors: | Jee Suk Lee Young Hwa Soung Hong Jo Choi Taeg Kyu Kwon |
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Institution: | a Department of Anatomy and Cell Biology, Dong-A University College of Medicine and Medical Science Research Center, 3-1 Dongdaesin-dong, Seo-gu, Busan 602-714, South Korea b Department of General Surgery, Dong-A University College of Medicine, Busan, South Korea c Department of Oral Anatomy and Cell Biology, School of Dentistry, Pusan National University, 1-10 Ami-dong, Seo-gu, Busan, South Korea d Department of Immunology and Chronic Disease Research Center and Institute for Medical Science, School of Medicine, Keimyung University, 194 DongSan-Dong Jung-Gu, Taegu, South Korea |
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Abstract: | Bcl-2 protects tumor cells from the apoptotic effects of various antineoplastic agents. Increased expression of Bcl-2 has been associated with poor response to chemotherapy in various malignancies, including leukemia. Therefore, bypassing the resistance conferred by anti-apoptotic factors such as Bcl-2 represents an attractive therapeutic strategy against cancer cells, including leukemic cells. We undertook this study to examine whether SAHA (suberoylanilide hydroxamic acid) overcomes the resistance by Bcl-2 in human leukemic cells, with a specific focus on the involvement of PML-NBs. Experiments were conducted with Bcl-2-overexpressing human leukemic U937 cells. Since we previously demonstrated that overexpression of Bcl-2 attenuates resveratrol-induced apoptosis in human leukemic U937 cells, resveratrol-treated U937 cells were used as a negative control. The present study indicates that SAHA at 1-7 μM, the dose range known to induce apoptosis in various cancer cells, overcomes the anti-apoptotic effects of Bcl-2 in Bcl-2-overexpressing human leukemic U937 cells. Notably, we observed that SAHA-induced formation of mature promyelocytic leukemia (PML) nuclear bodies (NBs) correlates with overcoming the anti-apoptotic effects of Bcl-2 in human leukemic U937 cells. Thus, PML protein and the formation of mature PML-NBs could be considered as therapeutic targets that could help bypass the resistance to apoptosis conferred by Bcl-2. Elucidating exactly how PML regulates Bcl-2 will require further work. |
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Keywords: | HDACIs histone deacetylase inhibitors SAHA suberoylanilide hydroxamic acid PML promyelocytic leukemia NBs nuclear bodies DMSO dimethyl sulfoxide FBS fetal bovine serum DiOC6 3 3&prime -dihexyloxacarbocyanine iodide FITC fluorescein isothiocyanate PI propidium iodine PARP poly(ADP-ribose)polymerase ECL enhanced chemiluminescence |
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