Apicidin

Apicidin, a natural fugal metabolite, is a selective inhibitor of HDAC.
Histone deacetylases (HDAC) are enzymes that remove acetyl groups from an ε-N-acetyl lysine amino acid on a histone. It has been revealed that histone acetyltransferase and histone deacetylase play important roles to either transcriptionally activate or repress gene expression through the reversible acetylation of lysine residues on a histone.
Apicidin has the potent and broad activity against apicomplexan parasites [1]. It has also been shown to have potent anti-angiogenesis activity and decrease HIF-1a levels in both human and mouse cancer cell lines [2].
The component has also been used extensively in vivo study to understand the role of HDAC in different physical processes. Apicidin exhibits anti-proliferative activity against different cancer cells lines in mice [3]. In a human colon HCT-116 carcinoma xenograft model, apicidin suppresses the tumor growth [4]. And it also exhibits the antitumor activity in a Ishikawa cell tumor xenograft model [5].
References:
1.Darkin-Rattray SJ, Gurnett AM, Myers RW, Dulski PM, Crumley TM, Allocco JJ, et al. Apicidin: a novel antiprotozoal agent that inhibits parasite histone deacetylase. Proc Natl Acad Sci U S A 1996,93:13143-13147.
2.Kim SH, Jeong JW, Park JA, Lee JW, Seo JH, Jung BK, et al. Regulation of the HIF-1alpha stability by histone deacetylases. Oncol Rep 2007,17:647-651.
3.Han JW, Ahn SH, Park SH, Wang SY, Bae GU, Seo DW, et al. Apicidin, a histone deacetylase inhibitor, inhibits proliferation of tumor cells via induction of p21WAF1/Cip1 and gelsolin. Cancer Res 2000,60:6068-6074.
4.Jones P, Altamura S, De Francesco R, Paz OG, Kinzel O, Mesiti G, et al. A novel series of potent and selective ketone histone deacetylase inhibitors with antitumor activity in vivo. J Med Chem 2008,51:2350-2353.
5.Ahn MY, Chung HY, Choi WS, Lee BM, Yoon S, Kim HS. Anti-tumor effect of apicidin on Ishikawa human endometrial cancer cells both in vitro and in vivo by blocking histone deacetylase 3 and 4. Int J Oncol 2010,36:125-131.

In vitro cytotoxicity evaluation of HDAC inhibitor Apicidin in pancreatic carcinoma cells subsequent time and dose dependent treatment.[Pubmed:25917448]

Toxicol Lett. 2015 Jul 2;236(1):8-15.

Apicidin is a potent histone deacetylase inhibitor (HDACI) that selectively binds to histone deacetylases (HDACs) class I and interferes with the deacetylation process, which results in modification of acetylation level of cellular proteins. The aim of the study was to investigate the potential time and dose dependent cytotoxicity of the test compound, Apicidin, in pancreatic cancer cells Capan-1 and Panc-1 as well as estimate maximal tolerable dose (MTD) of the test agent and determine EC50 using four complementary colorimetric cytotoxicity or viability assays. The cells were treated with increasing concentrations of Apicidin (0-5000nM) for 2, 4 and 6h (short term exposure) or 24, 48 and 72h (long term exposure) before conducting cytotoxic analyses with lactate dehydrogenase assay or viability analyses with sulforhodamine B (SRB), methyl tetrazolium (MTT) and crystal violet (CV) assays. In order to investigate whether Apicidin irreversibly affects the cells already during the short term exposure, the medium containing Apicidin was removed and replaced with fresh culturing medium after 6h of treatment. The cells were then incubated for additional 24, 48 or 72h before carrying out the analysis. The results obtained from cytotoxicity and viability assays indicated, that Apicidin was well tolerated by both cell lines at concentrations below 100nM at any given time point and at all applied concentrations during the short term (6h or less) treatment. Continuous prolonged term exposures (48h or greater) of the cells to Apicidin with concentration exceeding 100nM resulted in significantly increasing cytotoxicity and sustained significant loss of cell viability. Moreover, long term exposure of pancreatic cancer cells Capan-1 and Panc-1 to Apicidin concentrations exceeding 100nM showed an initial anti-proliferative effect before cytotoxicity onset. In summary, MTD was exposure time dependent and estimated to 100nM for long term treatment and to at least 5000nM for treatment not greater than 6h. EC50 concentration of Apicidin was established after long term treatment, however with some variation when comparing the different assays and cell lines. Results from this study may encourage reinvestigating the capacity of potent HDACI Apicidin as an attractive agent for interfering with the deacetylation process catalyzed by HDACs for potential pancreatic cancer intervention.

Apicidin inhibits cell growth by downregulating IGF-1R in salivary mucoepidermoid carcinoma cells.[Pubmed:25647264]

Oncol Rep. 2015 Apr;33(4):1899-907.

Inhibition of histone deacetylases (HDACs) has emerged as a new target for cancer therapies. The present study examined the antitumor effect and molecular mechanism of the HDAC inhibitor Apicidin in YD-15 human salivary mucoepidermoid carcinoma (MEC) cells. The cells were treated with Apicidin and cell death was quantified using an MTT assay. Apoptosis and autophagy were measured using flow cytometry, immunoblot analysis and cell staining. Regulation of the signaling pathways was monitored using immunoblot analysis and co-treatment with specific inhibitors. Insulin-like growth factor 1 receptor (IGF-1R) was knocked down using specific siRNA. Apicidin significantly inhibited the proliferation of MEC cells. Apicidin also induced apoptosis through the inactivation of extracellular signal-regulated kinase (ERK) and AKT/mTOR signaling and activation of c-Jun NH2-terminal kinase (JNK), whereas Apicidin promoted autophagy through inactivation of the AKT/mTOR signaling. These effects may be mediated by the inhibition of IGF-1R, an upstream regulator of MAPK and AKT/mTOR pathways. These results suggested that Apicidin is an attractive chemotherapeutic agent against salivary MEC and may be a good candidate for targeting IGF-1R for cancer therapies.

Histone deacetylase inhibitor apicidin increases expression of the alpha-secretase ADAM10 through transcription factor USF1-mediated mechanisms.[Pubmed:28003340]

FASEB J. 2017 Apr;31(4):1482-1493.

ADAM10 (a disintegrin and metalloproteinase domain-containing protein 10) is the alpha-secretase that is involved in APP (beta-amyloid precursor protein) processing. Enhancement of the nonamyloidogenic APP pathway by ADAM10 provides therapeutic potential for Alzheimer's disease (AD). By using high-throughput screening that targeted ADAM10, we determined that Apicidin-an inhibitor of HDACs (histone deacetylases)-significantly increased mRNA and protein levels of ADAM10 in SH-SY5Y cells. A luciferase assay revealed that the nucleotides -444 to -300 in the ADAM10 promoter were sufficient to mediate this effect. In addition, knockdown of USF1 (upstream transcription factor 1) and HDAC2/3 prevented Apicidin regulation of ADAM10. Moreover, USF1 acetylation was increased by Apicidin, which enhanced the association of USF1 with HDAC2/3 and with the ADAM10 promoter. We further found that Apicidin did not affect the phosphorylation of ERK or USF1; however, ERK inhibitor U0126 blocked the effect of Apicidin on ADAM10. Finally, Apicidin increased the level of alpha-site C-terminal fragment from APP and reduced the production of beta-amyloid peptide 1-42. Collectively, our study provides evidence that ADAM10 expression can be regulated by HDAC2/3 inhibitor Apicidin via USF1-dependent mechanisms in which ERK signaling plays an important role. Thus, HDAC regulation of ADAM10 might shed new light on the understanding of AD pathology.-Hu, X.-T., Zhu, B.-L., Zhao, L.-G., Wang, J.-W., Liu, L., Lai, Y.-J., He, L., Deng, X.-J., Chen, G.-J. Histone deacetylase inhibitor Apicidin increases expression of the alpha-secretase ADAM10 through transcription factor USF1-mediated mechanisms.

Apicidin sensitizes pancreatic cancer cells to gemcitabine by epigenetically regulating MUC4 expression.[Pubmed:25275019]

Anticancer Res. 2014 Oct;34(10):5269-76.

BACKGROUND/AIM: Mucin 4 (MUC4) has been linked to resistance to gemcitabine in pancreatic cancer cells. The aim of the present study was to assess whether epigenetic control of MUC4 expression can sensitize pancreatic cancer cells to gemcitabine treatment. MATERIALS AND METHODS: A 76-member combined epigenetics and phosphatase small-molecule inhibitor library was screened for anti-proliferative activity against the MUC4(+) gemcitabine-resistant pancreatic cancer cell line Capan-1, followed by high-content screening of protein expression. RESULTS: Apicidin, a histone deacetylase inhibitor, showed the greatest anti-proliferative activity with a lethal dose 50 (LD50) value of 5.17 muM. Apicidin significantly reduced the expression of MUC4 and its transcription factor hepatocyte nuclear factor 4alpha. Combined treatment with a sub-therapeutic concentration of Apicidin and gemcitabine synergistically inhibited growth of Capan-1 cells. CONCLUSION: Apicidin appears to be a novel anti-proliferative agent against pancreatic cancer cells that may reverse chemoresistance by epigenetically regulating MUC4 expression.

Apicidin, a histone deaceylase inhibitor, induces both apoptosis and autophagy in human oral squamous carcinoma cells.[Pubmed:21856210]

Oral Oncol. 2011 Nov;47(11):1032-8.

Apicidin acts as a potent histone deacetylases (HDAC) inhibitor and the precise mechanism for its anti-tumor activity in human oral squamous cell carcinoma (OSCC) cells has not been examined. The aim of this study was to evaluate the anti-tumor efficacy of Apicidin through apoptosis and autophagy in OSCC cells. Cells were treated with Apicidin and cell death was quantified. Cell cycle and apoptosis were measured using flow cytometry assay, immunoblot. Autophagy was characterized by the increase of LC3B-II and the formation of acidic vesicular organelles (AVOs). Apicidin significantly inhibited the proliferation of OSCC cells in a dose-dependent manner. Apicidin markedly up-regulated p21(WAF1) led to G2/M phase arrest. Apicidin significantly increased the number of apoptotic cells compared to untreated control. Apicidin induced not only apoptosis but also autophagy in OSCC cells. Apicidin dramatically increased the levels of LC3 type II expression, ATG5 protein expression and the accumulation of AVOs. Inhibition of autophagy enhanced Apicidin-mediated cytotoxicity through an increase in apoptosis. These results suggest that Apicidin exerts anti-tumor effects by inducing apoptosis and autophagy and provide novel evidence of Apicidin-induced autophagy and autophagy inhibition enhances Apicidin-mediated apoptosis in OSCC cells.

Apicidin, a histone deacetylase inhibitor, inhibits proliferation of tumor cells via induction of p21WAF1/Cip1 and gelsolin.[Pubmed:11085529]

Cancer Res. 2000 Nov 1;60(21):6068-74.

Apicidin [cyclo(N-O-methyl-L-tryptophanyl-L-isoleucinyl-D-pipecolinyl -L-2-amino-8-oxodecanoyl)] is a fungal metabolite shown to exhibit antiparasitic activity by the inhibition of histone deacetylase (HDAC). In this study, we evaluated Apicidin as a potential antiproliferative agent. Apicidin showed a broad spectrum of antiproliferative activity against various cancer cell lines, although with differential sensitivity. The antiproliferative activity of Apicidin on HeLa cells was accompanied by morphological changes, cell cycle arrest at G1 phase, and accumulation of hyperacetylated histone H4 in vivo as well as inhibition of partially purified HDAC in vitro. In addition, Apicidin induced selective changes in the expression of p21WAF1/Cip1 and gelsolin, which control the cell cycle and cell morphology, respectively. Consistent with increased induction of p21WAF1/Cip1, phosphorylation of Rb protein was markedly decreased, indicating the inhibition of cyclin-dependent kinases, which became bound to p21WAF1/Cip1. The effects of Apicidin on cell morphology, expression of gelsolin, and HDAC1 activity in vivo and in vitro appeared to be irreversible, because withdrawal of Apicidin did not reverse those effects, whereas the induction of p21WAF1/Cip1 by Apicidin was reversible. Taken together, the results suggest that induction of histone hyperacetylation by Apicidin is responsible for the antiproliferative activity through selective induction of genes that play important roles in the cell cycle and cell morphology.

Apicidin: a novel antiprotozoal agent that inhibits parasite histone deacetylase.[Pubmed:8917558]

Proc Natl Acad Sci U S A. 1996 Nov 12;93(23):13143-7.

A novel fungal metabolite, Apicidin [cyclo(N-O-methyl-L-tryptophanyl-L -isoleucinyl-D-pipecolinyl-L-2-amino-8-oxodecanoyl)], that exhibits potent, broad spectrum antiprotozoal activity in vitro against Apicomplexan parasites has been identified. It is also orally and parenterally active in vivo against Plasmodium berghei malaria in mice. Many Apicomplexan parasites cause serious, life-threatening human and animal diseases, such as malaria, cryptosporidiosis, toxoplasmosis, and coccidiosis, and new therapeutic agents are urgently needed. Apicidin's antiparasitic activity appears to be due to low nanomolar inhibition of Apicomplexan histone deacetylase (HDA), which induces hyperacetylation of histones in treated parasites. The acetylation-deacetylation of histones is a thought to play a central role in transcriptional control in eukaryotic cells. Other known HDA inhibitors were also evaluated and found to possess antiparasitic activity, suggesting that HDA is an attractive target for the development of novel antiparasitic agents.

Apicidin (OSI 2040) is a fungal metabolite, acts as a histone deacetylase (HDAC) inhibitor, with antiparasitic activity and a broad spectrum antiproliferative activity.

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