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.
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.
Department of Clinical Pharmacotherapeutics, Tohoku Pharmaceutical University, Aoba-ku, Sendai 981-8558, Japan. syu-kan@tohoku-pharm.ac.jp
Syu-Ichi
S
Kanno
Naoyuki
N
Maeda
Ayako
A
Tomizawa
Shin
S
Yomogida
Tadashi
T
Katoh
Masaaki
M
Ishikawa
D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D045744:Cell Line, Tumor; D053144:Cell Nucleus Shape / Q000187:drug effects; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics / Q000378:metabolism*; D047630:Depsipeptides / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D056284:Histone Deacetylase 1 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006801:Humans; D015448:Leukemia, B-Cell / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D012333:RNA, Messenger / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors; D015854:Up-Regulation
D000970:Antineoplastic Agents; C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D047630:Depsipeptides; D056572:Histone Deacetylase Inhibitors; D012333:RNA, Messenger; C529984:spiruchostatin B; C110550:HDAC1 protein, human; D056284:Histone Deacetylase 1