Histone Deacetylase Inhibitors for Cancer Therapy

Kim, Tae You; Bang, Yung Jue; Robertson, Keith D.

doi:10.4161/epi.1.1.2644

Cited by 67 publications

(64 citation statements)

References 106 publications

(258 reference statements)

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“…Given that restoration of MHC-II expression by the HDAC inhibitor VPA suppressed tumor growth in F1-DcR3 mice, epigenetic regulation modifying TAM differentiation may be another important tumor-promoting mechanism that can targeted. It would be interesting to investigate whether the HDAC inhibitor, which has been applied in clinical cancer therapy (50), can synergistically enhance the efficacy of standard chemotherapy in patients whose tumors exhibit a high level of DcR3 expression. Although MMP2 and MMP9 are not critical for the protumoral effect in this study, the MMP inhibitor doxycycline (30 mg/kg/d) still contributes to the suppression of tumor growth in DcR3 mice (Supplemental Fig.…”

Section: Discussionmentioning

confidence: 99%

Decoy Receptor 3 Enhances Tumor Progression via Induction of Tumor-Associated Macrophages

Tai

Chang²,

Lan

et al. 2012

The Journal of Immunology

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Tumor-associated macrophages (TAMs) are the major component of tumor-infiltrating leukocytes. TAMs are heterogeneous, with distinct phenotypes influenced by the microenvironment surrounding tumor tissues. Decoy receptor 3 (DcR3), a member of the TNFR superfamily, is overexpressed in tumor cells and is capable of modulating host immunity as either a neutralizing decoy receptor or an effector molecule. Upregulation of DcR3 has been observed to correlate with a poor prognosis in various cancers. However, the mechanisms underlying the DcR3-mediated tumor-promoting effect remain unclear. We previously demonstrated that DcR3 modulates macrophage activation toward an M2-like phenotype in vitro and that DcR3 downregulates MHC class II expression in TAMs via epigenetic control. To investigate whether DcR3 promotes tumor growth, CT26-DcR3 stable transfectants were established. Compared with the vector control clone, DcR3-transfectants grew faster and resulted in TAM infiltration. We further generated CD68 promoter-driven DcR3 transgenic (Tg) mice to investigate tumor growth in vivo. Compared with wild-type mice, macrophages isolated from DcR3-Tg mice displayed higher levels of IL-10, IL-1ra, Ym1, and arginase activity, whereas the expression of IL-12, TNF-α, IL-6, NO, and MHC class II was downregulated. Significantly enhanced tumor growth and spreading were observed in DcR3-Tg mice, and the enhanced tumor growth was abolished by arginase inhibitor N-ω-hydroxy-l-norarginine and histone deacetylase inhibitor sodium valproate. These results indicated that induction of TAMs is an important mechanism for DcR3-mediated tumor progression. Our findings also suggest that targeting DcR3 might help in the development of novel treatment strategies for tumors with high DcR3 expression.

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Section: Discussionmentioning

confidence: 99%

Decoy Receptor 3 Enhances Tumor Progression via Induction of Tumor-Associated Macrophages

Tai

Chang²,

Lan

et al. 2012

The Journal of Immunology

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“…The regulation of DNA methylation by DNA methyltransferases (DNMTs) maintains cellular DNA stability and integrity and is the one of the major epigenetic mechanisms regulating the transcriptional activity of genes. DNMT inhibitors such as 5-azadeoxycytidine (5-aza) have been introduced as cancer therapeutics (27,28). However, the severe toxic effects and lack of gene specificity limit the application of these drugs.…”

Section: Introductionmentioning

confidence: 99%

Reserpine Inhibit the JB6 P+ Cell Transformation Through Epigenetic Reactivation of Nrf2-Mediated Anti-oxidative Stress Pathway

Bao

Zhang

et al. 2016

AAPS J

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Abstract. Nuclear factor erythroid-2 related factor 2 (Nrf2) is a crucial transcription factor that regulates the expression of defensive antioxidants and detoxification enzymes in cells. In a previous study, we showed that expression of the Nrf2 gene is regulated by an epigenetic modification. Rauvolfia verticillata, a traditional Chinese herbal medicine widely used in China, possesses anticancer and antioxidant effects. In this study, we investigated how Nrf2 is epigenetically regulated by reserpine, the main active component in R. verticillata, in mouse skin epidermal JB6 P+ cells. Reserpine induced ARE (antioxidant response element)-luciferase activity in HepG2-C8 cells. Accordingly, in JB6 P+ cells, it upregulated the mRNA and protein levels of Nrf2 and its downstream target genes heme oxygenase-1 (HO-1) and NAD(P)H:quinone oxidoreductase 1 (NQO1), while it only increased the protein level of UDP-glucuronosyltransferase 1A1 (UGT1A1). Furthermore, reserpine decreased the TPA (12-O-tetradecanoylphorbol-13-acetate)-induced colony formation of JB6 cells in a dosedependent manner. DNA sequencing and methylated DNA immunoprecipitation further demonstrated the demethylation effect of reserpine on the first 15 CpGs of the Nrf2 promoter in JB6 P+ cells. Reserpine also reduced the mRNA and protein expression of DNMT1 (DNA methyltransferase 1), DNMT3a (DNA methyltransferases 3a), and DNMT3b (DNA methyltransferases 3b). Moreover, reserpine induced Nrf2 expression via an epigenetic pathway in skin epidermal JB6 P+ cells, enhancing the protective antioxidant activity and decreasing TPA-induced cell transformation. These results suggest that reserpine exhibits a cancer preventive effect by reactivating Nrf2 and inducing the expression of target genes involved in cellular protection, potentially providing new insight into the chemoprevention of skin cancer using reserpine.

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“…116 Specifically, hyperacetylation of HSP90 by HDAC inhibitors leads to the destabilization of HSP90-client protein complexes and achieves similar effects as HSP90 inhibitors. The transcriptional and nontranscriptional effects of HDAC inhibitors render this class of agents attractive for clinical development as drugs that target multiple pathways.…”

Section: Histone Deacetylases Inhibitorsmentioning

confidence: 99%

Novel Agents on the Horizon for Cancer Therapy

Wen¹,

Adjei²

2009

CA: A Cancer Journal for Clinicians

281

200

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Although cancer remains a devastating diagnosis, several decades of preclinical progress in cancer biology and biotechnology have recently led to successful development of several biological agents that substantially improve survival and quality of life for some patients. There is now a rich pipeline of novel anticancer agents in early phase clinical trials. The specific tumor and stromal aberrancies targeted can be conceptualized as membrane-bound receptor kinases (HGF/c-Met, human epidermal growth factor receptor and insulin growth factor receptor pathways), intracellular signaling kinases (Src, PI3k/Akt/mTOR, and mitogen-activated protein kinase pathways), epigenetic abnormalities (DNA methyltransferase and histyone deacetylase), protein dynamics (heat shock protein 90, ubiquitin-proteasome system), and tumor vasculature and microenvironment (angiogenesis, HIF, endothelium, integrins). Several technologies are available to target these abnormalities. Of these, monoclonal antibodies and small-molecule inhibitors have been the more successful, and often complementary, approaches so far in clinical settings. The success of this target-based cancer drug development approach is discussed with examples of recently approved agents, such as bevacizumab, erlotinib, trastuzumab, sorafenib, and bortezomib. This review also highlights the pipeline of rationally designed drugs in clinical development that have the potential to impact clinical care in the near future.

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Histone Deacetylase Inhibitors for Cancer Therapy

Cited by 67 publications

References 106 publications

Decoy Receptor 3 Enhances Tumor Progression via Induction of Tumor-Associated Macrophages

Decoy Receptor 3 Enhances Tumor Progression via Induction of Tumor-Associated Macrophages

Reserpine Inhibit the JB6 P+ Cell Transformation Through Epigenetic Reactivation of Nrf2-Mediated Anti-oxidative Stress Pathway

Novel Agents on the Horizon for Cancer Therapy

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