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Synergistic activity of bortezomib and HDACis in preclinical models of B-cell precursor acute lymphoblastic leukemia via modulation of p53, PI3K/AKT and NF-κB

Item Type:Article
Title:Synergistic activity of bortezomib and HDACis in preclinical models of B-cell precursor acute lymphoblastic leukemia via modulation of p53, PI3K/AKT and NF-κB
Creators Name:Bastian, L. and Hof, J. and Pfau, M. and Fichtner, I. and Eckert, C. and Henze, G. and Prada, J. and von Stackelberg, A. and Seeger, K. and Shalapour, S.
Abstract:PURPOSE: Relapse of disease and subsequent resistance to established therapies remains a major challenge in the treatment of childhood B-cell precursor acute lymphoblastic leukemia (BCP-ALL). New therapeutic options, such as proteasome and histone deacetylase inhibitors (HDACis) with a toxicity profile differing from that of conventional cytotoxic agents are needed for these extensively pre-treated patients. EXPERIMENTAL DESIGN: Anti-proliferative and pro-apoptotic effects of combined HDACi/proteasome inhibitor treatments were analyzed using BCP-ALL monocultures, cocultures with primary mesenchymal stroma cells from ALL-patients and xenograft mouse models. The underlying molecular mechanisms associated with combined treatment were determined by gene expression profiling and protein validation. RESULTS: We identified the proteasome inhibitor bortezomib (BTZ) as a promising combination partner for HDACis due to the substantial synergistic antileukemic activity in BCP-ALL cells after concomitant application. This effect was maintained or even increased in the presence of chemotherapeutic agents. The synergistic effect of combined HDACi/BTZ treatment was associated with the regulation of genes involved in cell cycle, JUN/MAPK-, PI3K/AKT-, p53-, ubiquitin-proteasome and NF-{kappa}B pathways. We observed an activation of NF-{kappa}B after BTZ treatment and the induction of apoptosis-related NF-{kappa}B target genes such as TNF{alpha}Rs after concomitant treatment, indicating a possible involvement of NF-{kappa}B as pro-apoptotic mediator. In this context, significantly lower NF-{kappa}B subunits gene expression was detected in leukemia cells from patients, who developed a relapse during frontline chemotherapy, compared to those who relapsed after cessation of frontline therapy. CONCLUSION: These results provide a rationale for the integration of HDACi/BTZ combinations into current childhood BCP-ALL treatment protocols.
Keywords:Antineoplastic Agents, Apoptosis, B-Cell Leukemia, Boronic Acids, Cultured Tumor Cells, Drug Synergism, Histone Deacetylase Inhibitors, NF-kappa B, Phosphatidylinositol 3-Kinases, Precursor Cell Lymphoblastic Leukemia-Lymphoma, Proto-Oncogene Proteins c-Akt, Pyrazines, Transcription Factor RelA, Tumor Suppressor Protein p53, Xenograft Model Antitumor Assays, Animals, Mice
Source:Clinical Cancer Research
Publisher:American Association for Cancer Research
Page Range:1445-1457
Date:15 March 2013
Official Publication:https://doi.org/10.1158/1078-0432.CCR-12-1511
PubMed:View item in PubMed

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