草苔虫内酯5通过激活PUMA和caspases诱导急性单核细胞性白血病细胞凋亡
Acute leukemia is a malignant clonal hematopoietic stem cell disease.It occurs in all age groups,and has the highest mortality of all malignant tumors in children and people younger than 35 years old.There is a need for novel anti-leukemia agents due to toxicity and resistance to existing chemotherapeutic agents.In the present study,we examined the effects of bryostatin 5 on primary acute monocytic leukemia cells and the U937 acute monocytic leukemia cell line.We also explored the apoptotic mechanisms and pathways induced by bryostatin 5,especially its interactions with the BH3-only proteins (PUMA and Bcl-XL) and the caspase proteins (caspase 3 and caspase 9).Bryostatin 5 inhibited the growth of primary acute monocytic leukemia cells and the U937 acute monocytic leukemia cell line.Cell cycle analysis showed that bryostatin 5 induced increasing in apoptotic cell numbers in U937 cells in dose- and time-dependent manners.TEM observation demonstrated some typical apoptotic characteristics on TEM,including chromatin condensation,karyopyknosis,and formation of crescents and apoptotic bodies,suggesting it induced apoptosis.Bryostatin 5 increased expression of PUMA and slightly increased P53 expression.Bcl-XL expression decreased significantly,accompanied by activation of caspases 9 and 3.Proapoptotic activity of bryostatin 5 in U937 cells was inhibited by specific PUMA siRNA and specific caspase 9 inhibitor.These results indicated that bryostatin 5 induced apoptosis through activation of PUMA gene and caspases.To the best of our knowledge,bryostatin 5 was the first small molecule shown to act on the PUMA gene.This study provided evidences to aid in the development of more effective anti-leukemia drugs and to identify new treatment strategies for leukemia.
acute monocytic leukemia bryostatin 5 apoptosis PUMA caspase
汤海峰 王一苇 林厚文 陈协群
第四军医大学西京医院药剂科,西安 710032;第四军医大学药学院药物研究所,西安 710032 第四军医大学西京医院血液内科,西安 710032 第二军医大学长征医院药学部,上海 200003
国内会议
南京
中文
1-13
2012-11-01（万方平台首次上网日期，不代表论文的发表时间）