Reddy P, Maeda Y, Hotary K, Liu C, Reznikov LL, Dinarello CA et al.. Histone deacetylase inhibitor suberoylanilide hydroxamic acid reduces acute graft-versus-host disease and preserves graft-versus-leuk. P Natl Acad Sci USA 101: 3921-3926

Department of Internal Medicine, University of Michigan Cancer Center, 1500 East Medical Center Drive, Ann Arbor, MI 48109-0942, USA.
Proceedings of the National Academy of Sciences (Impact Factor: 9.67). 04/2004; 101(11):3921-6. DOI: 10.1073/pnas.0400380101
Source: PubMed


Acute graft-versus-host disease (GVHD) and leukemic relapse are the two major obstacles to successful outcomes after allogeneic bone marrow transplantation (BMT), an effective therapy for hematological malignancies. Several studies have demonstrated that the dysregulation of proinflammatory cytokines and the loss of gastrointestinal tract integrity contribute to GVHD, whereas the donor cytotoxic responses are critical for graft-versus-leukemia (GVL) preservation. Suberoylanilide hydroxamic acid (SAHA) is currently in clinical trials as an antitumor agent; it inhibits the activity of histone deacetylases and at low doses exhibits antiinflammatory effects by reducing the production of proinflammatory cytokines. Using two well characterized mouse models of BMT, we have studied the effects of SAHA on GVHD severity and GVL activity. Administration of SAHA from day +3 to day +7 after BMT reduced serum levels of the proinflammatory cytokines and decreased intestinal histopathology, clinical severity, and mortality from acute GVHD compared with vehicle-treated animals. However, SAHA had no effect on donor T cell proliferative and cytotoxic responses to host antigens in vivo or in vitro. When mice received lethal doses of tumor cells at the time of BMT, administration of SAHA did not impair GVL activity and resulted in significantly improved leukemia-free survival by using two different tumor and donor/recipient combinations. These findings reveal a critical role for histone deacetylase inhibition in the proinflammatory events contributing to GVHD and suggest that this class of pharmacologic agents may provide a strategy to reduce GVHD while preserving cytotoxic T cell responses to host antigens and maintaining beneficial GVL effects.

    • "An increasing number of studies have shown that HDAC inhibitors have anti-inflammatory effects, in addition to their antitumor properties (Camelo et al., 2005; Chung et al., 2003; Glauben et al., 2006; Leng et al., 2006; Leoni et al., 2002; Reddy et al., 2004; Reilly et al., 2002). Vorinostat was the first HDAC inhibitor approved by the U.S. Food and Drug Administration for the treatment of cutaneous T cell lymphoma , and later for other cancers. "
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    ABSTRACT: Vorinostat, a histone deacetylase inhibitor, has been used clinically as an anticancer drug and also has immunosuppressive properties. However, the underlying mechanisms of effects of vorinostat on central nervous system (CNS) inflammatory diseases remain incomplete. Here, this study investigates the effects of vorinostat on human CD14(+) monocyte-derived dendritic cells (DCs) and mouse immature DC in vitro. Furthermore, we explore the therapeutic effects and cellular mechanisms of vorinostat on animal model of multiple sclerosis, experimental autoimmune encephalomyelitis (EAE) in vivo. Our findings demonstrate that vorinostat inhibited human CD14(+) monocyte-derived DCs differentiation, maturation, endocytosis, and further inhibited mDC's stimulation of allogeneic T-cell proliferation. In addition, vorinostat inhibited DC-directed Th1- (Type 1T helper) and Th17-polarizing cytokine production. Furthermore, vorinostat ameliorated Th1- and Th17-mediated EAE by reducing CNS inflammation and demyelination. What's more, Th1 and Th17 cell functions were suppressed in vorinostat-treated EAE mice. Finally, vorinostat suppressed expression of costimulatory molecules of DC in EAE mice. These suggest therapeutic effects of vorinostat on EAE which may by suppress DCs and DCs-mediated Th1 and Th17 cell functions. Our findings warrant further investigation in the potential of vorinostat for the treatment of human multiple sclerosis.
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    • "However, in two mouse models, administration of vorinostat after allogenic bone marrow transplantation led to a reduced acute mortality due to graft-versus-host disease (GvHD). By contrast, a stable graft-versus-leukaemia (GvL) activity was observed in addition to a reduction of proinflammatory cytokines (Reddy et al, 2004). Based on these findings, clinical trials to assess the potential of HDACi as supportive treatment after haematopoietic stem cell transplantation have already been initiated (NCT01451268, NCT00810602). "
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    ABSTRACT: The last three decades of cancer research were guided by the hypothesis that cancer cells evolve due to the accumulation of many genetic aberrations over time. While this is still true for most solid cancers, it might be different in haemato-malignant diseases, which are mostly characterized by chromosomal translocations that exhibit only few additional mutations. Some of the resulting fusion gene products functionally interfer with epigenetic mechanisms. Recent findings of mutated IDH1, IDH2, DNMT3A or TET2 in myelodysplastic syndrome/acute myeloid leukaemia patients underscore this notion, and point to the importance of epigenetic changes for developing tumour cells. This review aims (i) to give an overview about the different components of the epigenetic system, (ii) to describe the functions of different proteins or complexes that are involved in setting-up the epigenetic layer, (iii) to highlight some recent findings, and (iv) to describe the failures and successes when using drugs that are targeting epigenetic components.
    Full-text · Article · Jun 2012 · British Journal of Haematology
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    • "In bone marrow transplantation mouse model, addition of SAHA day +3 to +7 after transplantation prevents gastrointestinal tract damage by reducing cytokine release of TNF-α, IFN-γ and IL-1 in a dose-dependent manner. When compared with allogeneic controls, mortality and grade of acute GvHD were reduced corresponding to significantly improved survival (Reddy et al. 2004). Surprisingly, prophylactic treatment with SAHA did not alter cytotoxic T cell reaction against host antigens and thereby preserved GvL effect. "

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