title: 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.
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 microM, 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.
authors.affiliation: Department of Anatomy and Cell Biology, Dong-A University College of Medicine and Medical Science Research Center, 3-1 Dongdaesin-dong, Seo-gu, Busan, South Korea.
authors.forename: Jee Suk
authors.initials: JS
authors.lastname: Lee
authors.forename: Seung Hun
authors.initials: SH
authors.lastname: Jeong
authors.forename: Young Hwa
authors.initials: YH
authors.lastname: Soung
authors.forename: Tae Hyun
authors.initials: TH
authors.lastname: Kim
authors.forename: Hong Jo
authors.initials: HJ
authors.lastname: Choi
authors.forename: Bong Soo
authors.initials: BS
authors.lastname: Park
authors.forename: Taeg Kyu
authors.initials: TK
authors.lastname: Kwon
authors.forename: Young Hyun
authors.initials: YH
authors.lastname: Yoo
mesh_terms: D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D015153:Blotting, Western; D053148:Caspase 3 / Q000378:metabolism; D004591:Electrophoresis, Polyacrylamide Gel; D005455:Fluorescent Antibody Technique; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology*; D045586:Intranuclear Inclusion Bodies / Q000187:drug effects*; D007938:Leukemia / Q000473:pathology; D008564:Membrane Potentials / Q000187:drug effects; D018613:Microscopy, Confocal; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000037:antagonists & inhibitors / Q000502:physiology*; D020298:U937 Cells; D000077337:Vorinostat
chemical_list: D006877:Hydroxamic Acids; D019253:Proto-Oncogene Proteins c-bcl-2; D000077337:Vorinostat; D053148:Caspase 3