3-deazaneplanocin A: A new inhibitor of S-adenosylhomocysteine synthesis and its effects in human colon carcinoma cells

Glazer, Robert I.; Knode, Marian C.; Tseng, Christopher K. H.; Haines, David R.; Márquez, Víctor E.

doi:10.1016/0006-2952(86)90774-4

Cited by 70 publications

(37 citation statements)

References 20 publications

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“…When applied in combination with a histone deacetylase (HDAC) inhibitor, DZNep caused massive apoptosis induction upon the restoration of DACT3 expression, ultimately allowing Dishevelled activation. DZNep has been initially characterized as an S-adenosylhomocysteine hydrolase inhibitor, indirectly causing histone methyltransferase inhibition (52)(53)(54). Although DZNep has limited clinical potential due to its untargeted, global methyltransferase inhibitory effects (54), its uses in fundamental studies on cancer epigenetics paved the road for the development of other potent EZH2 inhibitors (46)(47)(48)53).…”

Section: Prc2 Alters Gsk3 Activity In Human Cancersmentioning

confidence: 99%

Molecular Pathways: Epigenetic Modulation of Wnt–Glycogen Synthase Kinase-3 Signaling to Target Human Cancer Stem Cells

Benoit

Guezguez

Boyd

et al. 2014

Clinical Cancer Research

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Aberrant regulation of the canonical Wnt signaling pathway (Wnt-b-catenin-GSK3 axis) has been a prevalent theme in cancer biology since earlier observations until recent genetic discoveries gleaned from tumor genome sequencing. During the last few decades, a large body of work demonstrated the involvement of the Wnt-b-catenin-GSK3 signaling axis in the formation and maintenance of cancer stem cells (CSC) responsible for tumor growth in several types of human malignancies. Recent studies have elucidated epigenetic mechanisms that control pluripotency and stemness, and allow a first assessment on how embryonic and normal tissue stem cells are dysregulated in cancer to give rise to CSCs, and how canonical Wnt signaling might be involved. Here, we review emerging concepts highlighting the critical role of epigenetics in CSC development through abnormal canonical Wnt signaling. Finally, we refer to the characterization of novel and powerful inhibitors of chromatin organization machinery that, in turn, restore the Wnt-b-catenin-GSK3 signaling axis in malignant cells, and describe attempts/relevance to bring these compounds into preclinical and clinical studies.

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Section: Prc2 Alters Gsk3 Activity In Human Cancersmentioning

confidence: 99%

Molecular Pathways: Epigenetic Modulation of Wnt–Glycogen Synthase Kinase-3 Signaling to Target Human Cancer Stem Cells

Benoit

Guezguez

Boyd

et al. 2014

Clinical Cancer Research

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“…With the aim of finding new prevention combinations, we studied the effect of cotreatment with 3-deazaneplanocin (DZNep) and EGCG on the skin cancer cells. DZNep, a deazaadenosine analog, is an inhibitor of the enzyme S-adenosyl homocysteine (AdoHcy) hydrolase (109)(110)(111). Inhibition of this enzyme results in accumulation of AdoHcy which limits the methyl groups available for use by S-adenosyl-L-methionine-dependent methyl transferases (111).…”

Section: Epigenetic Impact Of Dietary Agents (Sulforaphane and Green mentioning

confidence: 99%

Epigenetic Cancer Prevention Mechanisms in Skin Cancer

Saha

Hornyak

Eckert

2013

AAPS J

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Abstract. Epigenetics is an important emerging area for study of mechanisms of cancer prevention. In recent years, it has been realized that cancer prevention agents, derived from natural dietary sources, impact cancer cell survival by modulating epigenetic processes. In the present manuscript, we review key epigenetic regulatory mechanisms and examine the impact of sulforaphane and green tea polyphenols on these processes. We also discuss available information on the epigenetics in the context of skin cancer. These studies indicate that diet-derived chemopreventive agents modulate DNA methylation status and histone modification via multiple processes and point to additional areas for study of epigenetic mechanisms in skin cancer.

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“…For this reason, 3-deazaneplanocin A and the "decapitated" analogs of neplanocin A and 3-deazaneplanocin A, referred to as DHCA [9-(trans-2',trans-3'-dihydroxycyclopent-4'-enyl)adenine] and DHCDA [9-(trans-2',trans-3'-dihydroxycyclopent-4'-enyl)-3-deazaadenine], were synthesized (3,15,22). Both DHCA and DHCDA were indeed more selective in their activity against vaccinia virus than neplanocin A was (16).…”

Section: * Corresponding Authormentioning

confidence: 99%

“…We have now extended these studies to a broad range of DNA and RNA viruses. In addition to DHCA, DHCDA, and neplanocin A, we included in our investigation 3-deazaneplanocin A, which is also assumed to be a potent inhibitor of AdoHcy hydrolase but with a lower degree of cytotoxicity than neplanocin A (13,15). The structural formulae of the compounds are depicted in Fig.…”

Section: * Corresponding Authormentioning

confidence: 99%

Broad-spectrum antiviral activities of neplanocin A, 3-deazaneplanocin A, and their 5'-nor derivatives

Clercq

Cools

Balzarini

et al. 1989

Antimicrob Agents Chemother

103

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The neplanocin A analogs, 3-deazaneplanocin A, 9-(trans-2',trans-3'-dihydroxycyclopent-4'-enyl)adenine (DHCA), and 9-(trans-2',trans-3'-dihydroxycyclopent-4'-enyl)-3-deazaadenine (DHCDA), all potent inhibitors of S-adenosylhomocysteine (AdoHcy) hydrolase, were studied for their broad-spectrum antiviral potential. 3-Deazaneplanocin A, DHCA, and DHCDA proved specifically effective against vesicular stomatitis virus, vaccinia virus, parainfluenza virus, reovirus, and rotavirus. Their selectivity was greater than that of neplanocin A, particularly against vesicular stomatitis virus and rotavirus. As could be expected from adenosine analogs that are directly targeted at AdoHcy hydrolase, 3-deazaneplanocin A, DHCA, and DHCDA were fully active in adenosine kinase-deficient cells, implying that their activity did not depend on phosphorylation by adenosine kinase. None of the AdoHcy hydrolase inhibitors showed selective activity against human immunodeficiency virus (type 1). 3-Deazaneplanocin A at a dose of 0.5 mg/kg per day conferred marked protection against a lethal infection of newborn mice with vesicular stomatitis virus.Neplanocin A is a potent antiviral agent active against a broad spectrum of viruses belonging to the Poxviridae, Rhabdoviridae, Paramyxoviridae, and Reoviridae (6). It is particularly effective against vaccinia virus, vesicular stomatitis virus, parainfluenza virus, measles virus, reovirus (6), and human rotavirus (20). Neplanocin A is a potent inhibitor of S-adenosylhomocysteine (AdoHcy) hydrolase, a key enzyme in transmethylation reactions depending on S-adenosylmethionine as the methyl donor (2). As such, transmethylation reactions play an important role in the maturation (e.g., 5' capping) of viral mRNA, and AdoHcy hydrolase has been considered to be an important target enzyme for broad-spectrum antiviral agents (7). In fact, a close correlation has been found between the antiviral effects of a series of adenosine analogs, including neplanocin A, and their inhibitory effects on AdoHcy hydrolase (4, 9).Although antivirally active at concentrations which are well below its toxicity threshold for the host cells (6), neplanocin A is definitely cytotoxic for a number of tumor cells (18,24). This cytotoxicity may be attributed to the fact that the compound is readily phosphorylated to its triphosphate (1, 24), which then interferes with host-cell RNA synthesis (18). Neplanocin A triphosphate could be further metabolized to S-neplanocylmethionine (14,19), and this metabolite may also play an important role in the cytotoxic action of the compound (14). If the hypothesis is correct that the antiviral action of neplanocin A is due to an inhibitory effect of the compound per se on AdoHcy hydrolase, whereas its cytotoxic action depends upon phosphorylation to the corresponding triphosphate, it should be possible to design neplanocin A analogs that are endowed with antiviral properties while lacking cytotoxicity, thus achieving a better therapeutic index than that of neplanocin A itself. * Corresponding auth...

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3-deazaneplanocin A: A new inhibitor of S-adenosylhomocysteine synthesis and its effects in human colon carcinoma cells

Cited by 70 publications

References 20 publications

Molecular Pathways: Epigenetic Modulation of Wnt–Glycogen Synthase Kinase-3 Signaling to Target Human Cancer Stem Cells

Molecular Pathways: Epigenetic Modulation of Wnt–Glycogen Synthase Kinase-3 Signaling to Target Human Cancer Stem Cells

Epigenetic Cancer Prevention Mechanisms in Skin Cancer

Broad-spectrum antiviral activities of neplanocin A, 3-deazaneplanocin A, and their 5'-nor derivatives

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