Cotreatment with the histone deacetylase inhibitor suberoylanilide hydroxamic acid (SAHA) enhances imatinib-induced apoptosis of Bcr-Abl–positive human acute leukemia cells

Abstract

Here we demonstrate that treatment with SAHA (suberoylanilide hydroxamic acid), a known inhibitor of histone deacetylases (HDACs), alone induced p21 and/or p27 expressions but decreased the mRNA and protein levels of Bcr-Abl, which was associated with apoptosis of Bcr-Ablexpressing K562 and LAMA-84 cells. Cotreatment with SAHA and imatinib (Gleevec) caused more down-regulation of the levels and auto-tyrosine phosphorylation of Bcr-Abl and apoptosis of these cell types, as compared with treatment with either agent alone (P < .05). This finding was also associated with a greater decline in the levels of phospho-AKT and Bcl-x L . Significantly, treatment with SAHA also down-regulated Bcr-Abl levels and induced apoptosis of CD34 ؉ leukemia blast progenitor cells derived from patients who had developed progressive blast crisis (

Valproic acid inhibits proliferation and induces apoptosis in acute myeloid leukemia cells expressing P-gp and MRP1

“…Several authors showed recently that cotreatment with the HDAC inhibitor SAHA promoted STI571-mediated apoptosis in both STI571-sensitive and -resistant Bcr/ABL þ human myeloid leukemia cells. 16,17 At the same time, Peart et al 18 demonstrated that SAHA and oxamflatin, but not depsipeptide (all HDAC inhibitors), could kill P-gp þ cells. The results of our study show that VPA inhibits the proliferation of P-gp-and MRP1-expressing K562/DOX, HHT300, HL60/DNR and HL60/MRP cells as well as P-gp-and MRP1-nonexpressing K562S and HL60S cells.…”

Histone deacetylase inhibitors: molecular mechanisms of action

“…p27, which inhibits CDK4-and CDK2-containing complexes (Vidal and Koff, 2000), was induced by vorinostat and/or TSA, in leukemia cells K562 and LAMA-84 (Nimmanapalli et al, 2003), and breast cancer cells MCF-7 and MDA-MB-231 (Huang and Pardee, 2000). In cells cultured with HDACi, the increase of the CDK inhibitors and the decrease of cyclins may act together to account for the reduced CDK activity, causing dephosphorylation of retinoblastoma protein (Rb), which blocks E2F activities in the transcription of genes for G 1 progression and G 1 /S transition (Bolden et al, 2006).…”

“…Further, pretreament with HDACi had more effect (four times) than the reverse (1.8 times) in the combination with cisplatin, although the reverse was not antagonistic (Kim et al, 2003b). HDACi have also been reported to have synergy with transcription modulator all-trans retinoid acids, vitamin D3 and its analogs, DNA demethylating agent 5-aza-2 0 deoxycytidine, abl kinase inhibitor imatinib (Gleevec, STI571) in both imatinib-sensitive and imatinib-resistant chronic myelogenous leukemia (CML) cells, HSP90 inhibitor 17-ally-amino-demethoxy geldanamycin, proteasome inhibitor bortezomib (PS-341), trastuzumab (herceptin), which is a monoclonal antibody against Her-2/neu (erbB2) receptor, and radiotherapy (Nimmanapalli et al, 2003;Marks and Dokmanovic, 2005;Bolden et al, 2006). Upregulation of death receptors and/or reducing the inhibitory regulators of death receptor pathway by HDACi sensitize tumor cells to TRAIL (Bolden et al, 2006).…”

Histone Deacetylase Inhibitors for Cancer Therapy

“…LAQ824 treatment also reduced expression, promoted proteasomal degradation of Bcr-Abl, and induced apoptosis of imatinib-refractory chronic myelogenous leukemia. 101,102 In addition, LAQ824 depleted ErbB2 and sensitized breast cancer cells to the anti-Her2 antibody trastuzumab. 60 These various combination approaches appear to be advantageous, since HDACIs can be used at lower doses, thus reducing toxicity, and may also be useful in overcoming drug resistance.…”