Bryostatin 5 induces apoptosis in acute monocytic leukemia cells by activating PUMA and caspases.

Abstract

Acute leukemia is a malignant clonal hematopoietic stem cell disease. In the current study, we examined the effects of bryostatin 5 on acute monocytic leukemia cells in vitro and in vivo. We also explored the mechanisms and pathways underlying the increase in apoptosis induced by bryostatin 5. Bryostatin 5 inhibited the growth of primary acute monocytic leukemia cells and U937 cells in a dose- and time-dependent manners. Bryostatin 5 also induced an increase in apoptosis and a decrease in the mitochondrial membrane potential (MMP) in U937 cells. Transmission electron microscopy (TEM) revealed that bryostatin 5-treated cells displayed typical apoptotic characteristics (chromatin condensation, karyopyknosis and formation of crescents and apoptotic bodies). In addition, bryostatin 5 increased the expression of P53 upregulated modulator of apoptosis (PUMA) and slightly increased P53 expression. Bryostatin 5 also significantly decreased Bcl-XL expression and significantly increased the expression levels of Bak, Bax, cleaved caspase 9 and cleaved caspase 3. The pro-apoptotic activity of bryostatin 5 in U937 cells was inhibited by PUMA siRNA and z-LEHD-fmk (a specific caspase 9 inhibitor). In addition, the PUMA siRNA significantly affected the expression of cleaved caspase 9, whereas z-LEHD-fmk had little effect on the expression of PUMA. The results suggest that PUMA is located upstream of caspase 9 in this apoptotic signaling pathway. These novel findings provide mechanistic insight into the induction of apoptosis by bryostatin 5 and might facilitate the development of clinical strategies to enhance the therapeutic efficacy of treatments for acute monocytic leukemia.

• Authors: Yiwei Wang, Jinbao Zhang, Qixia Wang, Tao Zhang, Yang Yang, Yanghua Yi, Guangxun Gao, Hongjuan Dong, Huafeng Zhu, Yue Li, Houwen Lin, Haifeng Tang, Xiequn Chen
• Journal: European journal of pharmacology (Eur J Pharmacol) Vol. 718 Issue 1-3 Pg. 340-9 (Oct 15 2013) ISSN: 1879-0712 [Electronic] Netherlands
• PMID: 24036350 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2013 Elsevier B.V. All rights reserved.

Chemical References

• Antineoplastic Agents
• Apoptosis Regulatory Proteins
• BBC3 protein, human
• Bryostatins
• Caspase Inhibitors
• Proto-Oncogene Proteins
• RNA, Small Interfering
• Tumor Suppressor Protein p53
• bcl-X Protein
• bryostatin 5
• Caspases

Topics

• Animals
• Antineoplastic Agents (pharmacology)
• Apoptosis (drug effects)
• Apoptosis Regulatory Proteins (deficiency, genetics, metabolism)
• Bryostatins (pharmacology)
• Caspase Inhibitors (pharmacology)
• Caspases (metabolism)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Enzyme Activation (drug effects)
• Humans
• Leukemia, Monocytic, Acute (pathology)
• Male
• Membrane Potential, Mitochondrial (drug effects)
• Mice
• Proto-Oncogene Proteins (deficiency, genetics, metabolism)
• RNA, Small Interfering (genetics)
• Tumor Suppressor Protein p53 (metabolism)
• Xenograft Model Antitumor Assays
• bcl-X Protein (metabolism)