Differential sensitivity of human leukemic cell lines to the histone deacetylase inhibitor, trichostatin A.
Histone deacetylase inhibitors (HDACIs) inhibit deacetylases and the accumulation of high levels of acetylation results in chromatin remodeling events which may lead to cell cycle arrest and apoptosis. This work investigates the sensitivity of four leukemic cell lines to the HDACI, trichostatin A (TSA) as compared to normal lymphocytes with respect to acetylation and apoptotic levels. Specifically, this study analyzes the time kinetics of histone H4 and alpha-tubulin acetylation and associates these findings to the time course of TSA-induced PARP cleavage and DFF45 proteolysis. The results of this study show (1) that a non-responsive leukemic cell line to the apoptotic effects of TSA does not have increased acetylation levels in contrast to the responsive leukemic cell lines that show a hyperacetylated profile. This indicates that acetylation levels may be of special importance in accessing the potential sensitivities of leukemic cells to HDACIs, (2) TSA induced apoptosis in lymphocytes but at lower levels and (3) the lack of PARP cleavage and DFF45 proteolysis found in lymphocytes clearly differentiates the final stages apoptosis of human peripheral blood lymphocytes from those of the TSA-sensitive leukemic cell lines. Of value is that the results of this study show that the evaluation of the acetylation levels of target proteins may possibly have the potential of being used as additional indicators of the responsiveness or sensitivity of different cancer cell types to this continuously growing class of anticancer agents.
Ninios
Yiannis P
YP
Institute of Biology, National Centre for Scientific Research Demokritos, Attikis, Athens, Greece.
Sekeri-Pataryas
Kalliope E
KE
Sourlingas
Thomae G
TG
D000107:Acetylation / Q000187:drug effects; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D053938:DNA Fragmentation / Q000187:drug effects; D004353:Drug Evaluation, Preclinical; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D018922:HL-60 Cells; D051548:Histone Acetyltransferases / Q000378:metabolism; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006657:Histones / Q000378:metabolism; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology* / Q000627:therapeutic use; D020014:K562 Cells; D007938:Leukemia / Q000235:genetics / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D014404:Tubulin / Q000378:metabolism
D056572:Histone Deacetylase Inhibitors; D006657:Histones; D006877:Hydroxamic Acids; D014404:Tubulin; C012589:trichostatin A; D051548:Histone Acetyltransferases; D011065:Poly(ADP-ribose) Polymerases