Synthesis of 3-deazaneplanocin A, a powerful inhibitor of S-adenosylhomocysteine hydrolase with potent and selective in vitro and in vivo antiviral activities

Tumor cell plasticity contributes to functional and morphologic heterogeneity. To uncover the underlying mechanisms of this plasticity, we examined glioma stem-like cells (GSC) where we found that the biologic interconversion between GSCs and differentiated non-GSCs is functionally plastic and accompanied by gain or loss of polycomb repressive complex 2 (PRC2), a complex that modifies chromatin structure. PRC2 mediates lysine 27 trimethylation on histone H3 and in GSC it affected pluripotency or development-associated genes (e.g., Nanog, Wnt1, and BMP5) together with alterations in the subcellular localization of EZH2, a catalytic component of PRC2. Intriguingly, exogenous expression of EZH2-dNLS, which lacks nuclear localization sequence, impaired the repression of Nanog expression under differentiation conditions. RNA interference (RNAi)-mediated attenuation or pharmacologic inhibition of EZH2 had little to no effect on apoptosis or bromodeoxyuridine incorporation in GSCs, but it disrupted morphologic interconversion and impaired GSC integration into the brain tissue, thereby improving survival of GSC-bearing mice. Pathologic analysis of human glioma specimens revealed that the number of tumor cells with nuclear EZH2 is larger around tumor vessels and the invasive front, suggesting that nuclear EZH2 may help reprogram tumor cells in close proximity to this microenvironment. Our results indicate that epigenetic regulation by PRC2 is a key mediator of tumor cell plasticity, which is required for the adaptation of glioblastoma cells to their microenvironment. Thus, PRC2-targeted therapy may reduce tumor cell plasticity and tumor heterogeneity, offering a new paradigm for glioma treatment. Cancer Res; 73(14); 4559-70. Ó2013 AACR.

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“…Spectroscopic data of the synthesized DZNep were identical to those used in a previous study (26). 0 , Ver.…”

Section: -Deazaneplanocin a Treatment Of Cellsmentioning

confidence: 89%

“…3-Deazaneplanocin A (DZNep) was synthesized from a commercially available cyclopentenone derivative (CAS: 163317-01-9; CHEMSTEP) as described elsewhere (26). Spectroscopic data of the synthesized DZNep were identical to those used in a previous study (26).…”

Section: -Deazaneplanocin a Treatment Of Cellsmentioning

confidence: 99%

Chromatin Regulator PRC2 Is a Key Regulator of Epigenetic Plasticity in Glioblastoma

et al. 2013

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“…Instead, it is at least in part mediated through proteosomal degradation since proteosome inhibitors can restore PRC2 protein expression. Unlike 5-AzaC and zebularine that deplete DNMTs by incorporating and thus trapping them to the substituted DNA (Cheng et al 2004), DZNep is not phosphorylated and does not get incorporated into DNA (Glazer et al 1986;Tseng et al 1989). Thus it seems highly unlikely that DZNep depletes PRC2 proteins through a similar mechanism.…”

Section: Discussionmentioning

confidence: 99%

Pharmacologic disruption of Polycomb-repressive complex 2-mediated gene repression selectively induces apoptosis in cancer cells

Tan¹,

Yang²,

Li³

et al. 2007

Genes Dev.

819

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“…DZNep inhibits S-adenosyl-L-homocysteine hydrolase. 45 It induces accumulation of S-adenosyl-L-homocysteine, a by-product of S-adenosyl methionine (SAM)-dependent methylation, thereby, inhibiting methyltransferases. 45,46 It has also been shown to deplete EZH2 levels, thereby, inhibiting trimethylation of lysine 27 on histone H3 by blocking the polycomb-repressive-complex 2 in primary AML cells in a dose-dependent manner (0.2-1 mM).…”

mentioning

confidence: 99%

“…45 It induces accumulation of S-adenosyl-L-homocysteine, a by-product of S-adenosyl methionine (SAM)-dependent methylation, thereby, inhibiting methyltransferases. 45,46 It has also been shown to deplete EZH2 levels, thereby, inhibiting trimethylation of lysine 27 on histone H3 by blocking the polycomb-repressive-complex 2 in primary AML cells in a dose-dependent manner (0.2-1 mM). 47,48 Although both RA and DZNep inhibit MDSC suppressive functions, they did so in a qualitative and quantitative different manner ( Fig.…”

mentioning

confidence: 99%

Identification of inhibitors of myeloid-derived suppressor cells activity through phenotypic chemical screening

et al. 2016

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Tumors are infiltrated by cells of the immune system that interact through complex regulatory networks. Although tumor-specific CD8 C T cells can be found in peripheral blood and tumor samples from cancer patients, their function is inhibited by immunosuppressive cells such as regulatory T cells, tumorassociated macrophages, and myeloid-derived suppressor cells (MDSC). Recent clinical successes have demonstrated that alleviating immunosuppression and T cell exhaustion translates into long-term clinical benefits. Although tremendous progress has been achieved, tools that afford unbiased approaches and screenings to uncover new potential inhibitors or gene targets are lacking. In this study, we describe a system based on immortalized progenitors that allows straightforward investigation of myeloid cells. We show that bone marrow progenitors immortalized through the transduction of NUP98-HOXB4 transgene can be differentiated into CD11b C Gr-1 C MDSC that express Arginase-1 and PD-L1, produce reactive oxygen and nitrogen species, and suppress T cell function in vitro. To uncover chemical probes that interfere with MDSC biology, we performed a chemical phenotypic screening and identified 3-deazaneplanocin A as a novel modulator of MDSC functions. We characterized and compared the effect of 3-deazaneplanocin-A and all-trans retinoic acid, a well-known modulator of MDSC activity, on the expression of effector molecules and immunosuppressive functions of MDSC. Altogether, this proof-ofprinciple opens new possibilities for the identification of drugs targeting myeloid cells with immunosuppressive activities.

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Synthesis of 3-deazaneplanocin A, a powerful inhibitor of S-adenosylhomocysteine hydrolase with potent and selective in vitro and in vivo antiviral activities

Cited by 101 publications

References 3 publications

Chromatin Regulator PRC2 Is a Key Regulator of Epigenetic Plasticity in Glioblastoma

Chromatin Regulator PRC2 Is a Key Regulator of Epigenetic Plasticity in Glioblastoma

Pharmacologic disruption of Polycomb-repressive complex 2-mediated gene repression selectively induces apoptosis in cancer cells

Identification of inhibitors of myeloid-derived suppressor cells activity through phenotypic chemical screening

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