Involvement of p21waf1/cip1 expression in the cytotoxicity of the potent histone deacetylase inhibitor spiruchostatin B towards susceptible NALM-6 human B cell leukemia cells.

Abstract

Spiruchostatin B (SP-B) is a potent histone deacetylase (HDAC) inhibitor that has potential for the chemotherapy of leukemia. The aim of this study was to study the susceptibility of human leukemia cell lines to SP-B. We found that NALM-6 human B cell leukemia cells are the most susceptible to SP-B. There was a low correlation between the expression of HDAC1 mRNA and HDI susceptibility of leukemia cells. NALM-6 has higher endogenous p21waf1/cip1 mRNA expression than other leukemia cells. SP-B-induced cytotoxicity was mediated by induction of histone acetylation via inhibition of HDACs, and this effect of SP-B was associated with apoptosis, which was mediated by caspase activation in NALM-6 cells. SP-B time-dependently increased the size of the sub-G1 (apoptotic) peak, and this effect correlated with SP-B induction of cellular apoptotic features such as changes in nuclear morphology. SP-B significantly increased p21waf1/cip1 expression prior to induction of apoptosis. In conclusion, NALM-6 cells, which have a higher expression of p21waf1/cip1 mRNA than other leukemia cell lines, were susceptible to SP-B-induced cytotoxicity that resulted in induction of apoptosis. Our findings may be useful when establishing a therapeutic strategy based on SP-B.

• Authors: Syu-Ichi Kanno, Naoyuki Maeda, Ayako Tomizawa, Shin Yomogida, Tadashi Katoh, Masaaki Ishikawa
• Journal: International journal of oncology (Int J Oncol) Vol. 40 Issue 5 Pg. 1391-6 (May 2012) ISSN: 1791-2423 [Electronic] Greece
• PMID: 22211246 (Publication Type: Journal Article)

Chemical References

• Antineoplastic Agents
• CDKN1A protein, human
• Cyclin-Dependent Kinase Inhibitor p21
• Depsipeptides
• Histone Deacetylase Inhibitors
• RNA, Messenger
• spiruchostatin B
• HDAC1 protein, human
• Histone Deacetylase 1

Topics

• Antineoplastic Agents (pharmacology)
• Apoptosis (drug effects)
• Cell Cycle Checkpoints (drug effects)
• Cell Line, Tumor
• Cell Nucleus Shape (drug effects)
• Cyclin-Dependent Kinase Inhibitor p21 (genetics, metabolism)
• Depsipeptides (pharmacology)
• Dose-Response Relationship, Drug
• Gene Expression Regulation, Neoplastic (drug effects)
• Histone Deacetylase 1 (antagonists & inhibitors, genetics, metabolism)
• Histone Deacetylase Inhibitors (pharmacology)
• Humans
• Leukemia, B-Cell (enzymology, genetics, pathology)
• RNA, Messenger (metabolism)
• Signal Transduction (drug effects)
• Time Factors
• Up-Regulation