Trichostatin A inhibits proliferation and induces expression of p21WAF and p27 in human brain tumor cell lines.
OBJECTIVE
The histone deacetylase inhibitor, trichostatin A(TSA), was shown to induce apoptosis in transformed cells at submicromolar concentrations. However, the effect of TSA on brain tumor cells is still unknown. This study was designed to investigate whether TSA posses antitumor activity and if any, its mechanism.


METHODS
A p53 mutant human glioma cell line T98G and a p53 wild type human neuroblastoma cell line SKNSH were exposed to TSA. Cell proliferation was assessed by sulforhodamine B (SRB) cytotoxicity assay. Apoptosis was quantified by flow cytometry and confirmed by apoptotic ladder formation. Expression patterns of accumulation of highly acetylated histone H3, H4; p53 and cell cycle-associated p21waf, p27 which were induced by TSA were determined by using Western blot analysis.


RESULTS
TSA inhibited the proliferation of brain tumor cell lines at nanomolar concentrations and induced accumulation of highly acetylased histone moleculars. Treatment with TSA at 0.33 microM for 24 h significantly induced cell apoptosis. In addition to the suppression of cell growth, the up regulation of p21waf and p27 expression was observed within 48 h after the treatment. p21 protein levels were increased at early time points and reached maximal levels at 8 h, while p27 protein levels were increased after 8 h. However, there was no significant changes of acetylased p53 and endogenous p53 protein levels were observed.


CONCLUSIONS
TSA may inhibit brain tumor cell growth in vitro, which is otherwise particularly resistant to chemotherapy. TSA acts as an anti-tumor agent could be through co-operation between p21 and p27 in growth inhibition, irrespective of endogenous p53 status.
Wang
Zhi-min
ZM
Department of Neurosurgery, First Affiliated Hospital, Suzhou University, Suzhou 215006, P. R. China.
Hu
Jin
J
Zhou
Dai
D
Xu
Zhi-yuan
ZY
Panasci
Lwrence C
LC
Chen
Zhong-ping
ZP
D017209:Apoptosis / Q000187:drug effects; D018797:Cell Cycle Proteins / Q000096:biosynthesis / Q000187:drug effects*; D002455:Cell Division / Q000187:drug effects; D050759:Cyclin-Dependent Kinase Inhibitor p21; D050760:Cyclin-Dependent Kinase Inhibitor p27; D016213:Cyclins / Q000096:biosynthesis / Q000187:drug effects*; D053938:DNA Fragmentation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005910:Glioma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D056572:Histone Deacetylase Inhibitors; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology*; D013997:Time Factors; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis / Q000187:drug effects; D025521:Tumor Suppressor Proteins / Q000096:biosynthesis / Q000187:drug effects*
C493956:CDKN1A protein, human; D018797:Cell Cycle Proteins; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; D050760:Cyclin-Dependent Kinase Inhibitor p27; C012589:trichostatin A