PMID: 22338177Feb 18, 2012Paper

Reversal effect of LBH589 alone or in combination with bortezomib on drug-resistance in myeloid leukemia and its mechanism

Zhonghua xue ye xue za zhi = Zhonghua xueyexue zazhi
Xue-jie JiangWei-Wei Chen

Abstract

To investigate reversal effect of histone deacetylase inhibitor LBH589 alone or in combination with proteasome inhibitor bortezomib on drug resistance in acute myeloid leukemia (AML) and its mechanism. Ex vivo cultures of HL-60/ADM cells and fresh refractory AML cells were treated with LBH589, bortezomib or their combination at varying concentrations. Proliferation capacity, apoptosis rate and reversal of drug resistance were evaluated by MTT assay, dual staining of Hoechst 33342 and Annexin VFITC/PI by flow cytometry, and adriamycin uptake rate with proliferation inhibition, respectively. The change of signal pathway at protein level was analyzed by Western blot. Synergistic cytotoxicity was observed in the combination treatment with LBH589 and bortezomib against HL-60/ADM cells, as well as the fresh AML cells, the most powerful synergy being observed at 21 nmol/L LBH589 plus 12 nmol/L bortezomib, with CI values of 0.531 and 0.498, respectively by Calcusyn software analysis. Moreover, the accumulation of adriamycin in HL-60/ADM cells was increased more in combination treatment [(64.81 +/- 3.69)%] than in either LBH589 [(28.96 +/- 2.52)%] or bortezomib [(37.29 +/- 3.71)%] alone (P < 0.05), and so did the uptake rate of adriamyc...Continue Reading

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