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.
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.
Lee
Jee Suk
JS
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.
Jeong
Seung Hun
SH
Soung
Young Hwa
YH
Kim
Tae Hyun
TH
Choi
Hong Jo
HJ
Park
Bong Soo
BS
Kwon
Taeg Kyu
TK
Yoo
Young Hyun
YH
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
D006877:Hydroxamic Acids; D019253:Proto-Oncogene Proteins c-bcl-2; D000077337:Vorinostat; D053148:Caspase 3