Characterization of cells resistant to the potent histone deacetylase             inhibitor spiruchostatin B (SP-B) and effect of overexpressed p21waf1/cip1 on             the SP-B resistance or susceptibility of human leukemia cells.
We previously showed that the B cell leukemia cell line NALM-6 had the highest             susceptibility among a number of leukemia cell lines to spiruchostatin B (SP-B),             a potent histone deacetylase (HDAC) inhibitor. We also showed that SP-B-induced             cytotoxicity depended on induction of apoptosis that was mediated by p21waf1/cip1             expression. In the present study, we generated and characterized a stable, SP-B-resistant             NALM-6 cell line (NALM-6/SP-B) by continuous exposure to SP-B, starting with a             low SP-B concentration. NALM-6/SP-B cells were also more resistant to FK228, which             has a similar chemical structure to SP-B, and were slightly more resistant to             the P-gp substrates doxorubicin and vincristine than parental cells, but displayed             similar susceptibility to other HDAC inhibitors and to paclitaxel as the parental             cells. There was little change in the basal mRNA expression of HDAC1, p53, Bax,             Bcl-2, Fas, caspase-3, c-Myc and MDR1 in NALM-6/SP-B compared to parental cells,             but the mRNA expression of p21waf1/cip1 was decreased. The introduction of an             exogenous p21waf1/cip1 expression vector restored SP-B induction of NALM-6/SP-B             cell apoptosis. Moreover, overexpressed p21waf1/cip1 enhanced SP-B induction of             the apoptosis of the human erythroleukemia leukemia cell line K562 which is less             susceptible to SP-B than NALM-6 cells. These results suggest that downregulation             of p21waf1/cip1, which is a characteristic feature of NALM-6/SP-B cells, was important             for their resistance to SP-B, and that this SP-B resistance could be overcome             by the introduction of exogenous p21waf1/cip1. Furthermore, introduction of p21waf1/cip1             to other leukemia cells such as K562 may enhance their susceptibility to SP-B.             This is the first report of the characterization of SP-B-resistant cells and of             the effect of overexpressed p21waf1/cip1 on the resistance or susceptibility of             human leukemia cells to 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
D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics / Q000378:metabolism*; D047630:Depsipeptides / Q000494:pharmacology*; D004317:Doxorubicin / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm; D018014:Gene Transfer Techniques; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006655:Histone Deacetylases / Q000378:metabolism; D006801:Humans; D007938:Leukemia / Q000188:drug therapy*; D017239:Paclitaxel / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D014750:Vincristine / Q000494:pharmacology
D050759:Cyclin-Dependent Kinase Inhibitor p21; D047630:Depsipeptides; D056572:Histone Deacetylase Inhibitors; D012333:RNA, Messenger; C529984:spiruchostatin B; D014750:Vincristine; D004317:Doxorubicin; C087123:romidepsin; D006655:Histone Deacetylases; D017239:Paclitaxel