Effects of FK228, a novel histone deacetylase inhibitor, on human lymphoma U-937 cells in vitro and in vivo

Sasakawa, Yuka; Naoe, Yoshinori; Inoue, Takeshi; Sasakawa, Tatsuya; Matsuo, Makoto; Manda, Toshitaka; Mutoh, Seitaro

doi:10.1016/s0006-2952(02)01261-3

Cited by 92 publications

(62 citation statements)

References 52 publications

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“…Cyclin-dependent kinase inhibitor p21 WAF1 was clearly up-regulated and it has been reported to play an important role in growth arrest, both in G 1 and G 2 -M cell cycle arrest (29). Recent studies also reported that HDACIs exert cell cycle arrest by inducing p21 WAF1 in some other cell lines (15,17,18). HDACIs, such as trichostatin A, butyrate, suberoylanilide hydroxamic acid, and FK228, induce the acetylation of histones H3 and H4 in the promoter region including the Sp1-binding sites, also called the GC-box, which are important for the expression of the human p21 WAF1 gene (17 -20).…”

Section: Discussionmentioning

confidence: 99%

“…FK228 induces histone acetylation, cell cycle arrest, and differentiation or apoptosis in vitro and in vivo in some human cancer cell lines (13 -16). Recently, it was shown that HDACIs (e.g., FK228, suberoylanilide hydroxamic acid, and trichostatin A) activate transcription of the cyclin-dependent kinase inhibitor p21 WAF1 (15,17,18) and induction of p21 WAF1 by HDACIs requires the Sp-1 binding site and is associated with the accumulation of acetylated histones in the promoter region of the gene (17 -20).…”

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confidence: 99%

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Histone Deacetylase Inhibitor FK228 Activates Tumor Suppressor Prdx1 with Apoptosis Induction in Esophageal Cancer Cells

Hoshino

Matsubara

Hanari

et al. 2005

Clinical Cancer Research

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Purpose: The histone deacetylase inhibitor FK228 shows strong activity as a potent antitumor drug but its precise mechanism is still obscure. The purpose of this study is to reveal the effect of FK228 on gene expression in the cell and to determine the mechanism of the antitumor activity of FK228 for further clinical applications. Experimental Design and Results: Microarray analysis was applied to verify the gene expression profiles of 4,608 genes after FK228 treatment using human esophageal squamous cell cancer cell lines T.Tn and TE2. Among them, peroxiredoxin 1 (Prdx1), a member of the peroxiredoxin family of antioxidant enzymes having cell growth suppression activity, as well as p21 WAF1 , were significantly activated by FK288. In addition, FK228 strongly inhibited the cell growth of T.Tn and TE2 by the induction of apoptosis. Further, chromatin immunoprecipitation analysis revealed that FK228 induced the accumulation of acetylated histones H3 and H4 in Prdx1 promoter, including the Sp1-binding site. In mouse xenograft models of T.Tn and TE2 cells, FK228 injection resulted in significant tumor regression as well as activated Prdx1 expression in tumor tissues. Prdx1 suppression by RNA interference hindered the antitumor effect of FK228. Conclusion: Our results indicate that the antitumor effect of FK228 in esophageal cancer cells is shown at least in part through Prdx1 activation by modulating acetylation of histones in the promoter, resulting in tumor growth inhibition with apoptosis induction.

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Histone Deacetylase Inhibitor FK228 Activates Tumor Suppressor Prdx1 with Apoptosis Induction in Esophageal Cancer Cells

Hoshino

Matsubara

Hanari

et al. 2005

Clinical Cancer Research

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“…In these several studies, it has been found that HDACi induce about as many genes as are repressed. The cyclin-dependent kinase (CDK) inhibitor p21 (WAF1/CIP1) is one of the most common genes induced by HDACi (Archer et al, 1998;Richon et al, 2000;Sasakawa et al, 2002). HDACi-induced expression of p21 is independent of p53 and correlates with an increase in the acetylation of histones associated with the p21 promoter region (Richon et al, 2000;Gui et al, 2004).…”

Section: Hdaci Selectively Alters Gene Expressionmentioning

confidence: 99%

Histone deacetylase inhibitors: molecular mechanisms of action

2007

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“…[25] The amino acid based biphenyl bearing mercaptoacetamides were prepared as shown in Scheme 2. The biphenylamines 4a-e were coupled with 7-(2-tritylsulfanylacetylamino) heptanoic acid (8) [26] by PyBOP, followed by one pot deprotection of both the trityl and Boc groups of 9a-d with TFA/triethylsilane to afford the mercaptoacetamides 10a-d. Removal of the benzyl group in the tyrosine intermediate 9e using catalytic hydrogenation was sluggish, and extended reaction times led to cleavage of the thiol group to afford 11.…”

Section: Chemical Synthesismentioning

confidence: 99%

“…Indeed, chemical inhibitors of HDACs have been shown to inhibit tumor cell growth and induce differentiation and cell death. [5] Several such inhibitory agents, including suberoyanilide hydroxamic acid (SAHA, aka virinostat) and depsipeptide (FR901228) have reached clinical trials, [6][7][8] and SAHA has been approved by the FDA for use in cutaneous T-cell lymphoma (CTCL). The HDAC inhibitors (HDACIs) also enhance the cytotoxic effects of both radiation and chemotherapeutic drugs.…”

Section: Introductionmentioning

confidence: 99%

Chemistry, Biology, and QSAR Studies of Substituted Biaryl Hydroxamates and Mercaptoacetamides as HDAC Inhibitors—Nanomolar‐Potency Inhibitors of Pancreatic Cancer Cell Growth

et al. 2008

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The histone deacetylases (HDACs) are able to regulate gene expression and inhibitors of the HDACs (HDACIs) hold promise in the treatment of cancer as well as a variety of neurodegenerative diseases. To investigate the possibility to achieve some measure of isoform selectivity in the inhibition of the HDACs, we prepared a small series of 2,4′-diaminobiphenyl ligands functionalized at the para-amino group with an appendage containing either a hydroxamate or a mercaptoacetamide group and coupled to an amino acid residue at the ortho-amino group. A smaller series of substituted phenylthiazoles was also explored. Some of these newly synthesized ligands show low nM potency in the HDAC inhibition assays and display micromolar to low nanomolar IC 50 values when tested against five pancreatic cancer cell lines. The isoform selectivity of these ligands for the Class I HDACs (HDAC1-3 and 8) and Class IIb HDACs (HDAC6 and HDAC10) together with QSAR studies of their correlation with the lipophilicity are presented. Of particular interest is the HDAC6 selectivity of the mercaptoacetamides.

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Effects of FK228, a novel histone deacetylase inhibitor, on human lymphoma U-937 cells in vitro and in vivo

Cited by 92 publications

References 52 publications

Histone Deacetylase Inhibitor FK228 Activates Tumor Suppressor Prdx1 with Apoptosis Induction in Esophageal Cancer Cells

Histone Deacetylase Inhibitor FK228 Activates Tumor Suppressor Prdx1 with Apoptosis Induction in Esophageal Cancer Cells

Histone deacetylase inhibitors: molecular mechanisms of action

Chemistry, Biology, and QSAR Studies of Substituted Biaryl Hydroxamates and Mercaptoacetamides as HDAC Inhibitors—Nanomolar‐Potency Inhibitors of Pancreatic Cancer Cell Growth

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