The novel HDAC inhibitor AR-42-induced anti-colon cancer cell activity is associated with ceramide production

Xu, Weihong; Xu, Bin; Yao, Yiting; Yu, Xiaoling; Shen, Jie

doi:10.1016/j.bbrc.2015.05.078

Cited by 15 publications

(7 citation statements)

References 25 publications

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“…Interestingly, a study describing an HDAC6-independent Tubacin stimulatory effect on exosome biogenesis 45 led us to hypothesise that this phenotype may stem from the inhibition of MBLAC2, the only off-target of Tubacin in our chemoproteomic assay. Similarly, an unexplained phenotype was reported for AR42 64 , which we identi ed as a potent MBLAC2 inhibitor: AR42 leads to upregulation of ceramide levels 64 , a known trigger of exosome biogenesis 46 . Given that MBLAC2 can hydrolyze palmitoyl-CoA, the initial building block of ceramides, we speculated that MBLAC2 might be involved in regulating ceramide levels and exosome release.…”

Section: Discussionsupporting

confidence: 59%

Target deconvolution of HDAC pharmacopoeia highlights MBLAC2 as common off-target

Lechner

Malgapo

Grätz

et al. 2021

Preprint

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HDAC drugs have entered the pharmacopoeia in the 2000s. However, some enigmatic phenotypes suggest off-target engagement. Here, we developed a chemical proteomics assay using three promiscuous chemotypes and quantitative mass spectrometry that we deployed to establish the target landscape of 53 drugs. The results highlight 14 direct targets, including 9 out of the 11 human zinc-dependent HDACs, question the reported selectivity of widely-used molecules, notably for HDAC6, and delineate how the composition of HDAC complexes influences drug potency. Unexpectedly, metallo-beta-lactamase domain-containing protein 2 (MBLAC2) featured as a frequent target of hydroxamate drugs. This ill-annotated palmitoyl-CoA hydrolase is inhibited by 24 HDAC inhibitors at low nM potency. Both enzymatic inhibition and knocking down the protein led to the accumulation of extracellular vesicles. Given the importance of exosome biology in neurological diseases or cancer, this HDAC-independent drug effect creates the incentive for considering MBLAC2 as a target for drug discovery.

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Section: Discussionsupporting

confidence: 59%

Target deconvolution of HDAC pharmacopoeia highlights MBLAC2 as common off-target

Lechner

Malgapo

Grätz

et al. 2021

Preprint

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“…Elevation of Lnc-EPIC1 expression was detected as well in primary human colon cancer cells ( Figure 1B ). The primary cancer cells were derived from different human patients, pri-Can-1/-2/-3 (from Dr. Xu at Tong-ren Hospital [ 14 ]). Lnc-EPIC1 expression level is relatively low in NCM460 colon mucosa epithelial cells and primary human colon epithelial cells (“Colon Epi”) ( Figure 1B ).…”

Section: Resultsmentioning

confidence: 99%

Targeting LncRNA EPIC1 to inhibit human colon cancer cell progression

Wei

Chun-hua

et al. 2020

Aging

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Long non-coding RNA EPIC1 (Lnc-EPIC1) binds MYC protein, which is essential for MYC function and expression of MYC target genes. The current study tested its expression and potential functions in human colon cancer cells. We show that Lnc-EPIC1 expression is elevated in human colon cancer tissues and primary human colon cancer cells. Whereas its expression is relatively low in normal colon tissues and colon epithelial cells. In the primary human colon cancer cells, Lnc-EPIC1 siRNA largely inhibited cancer cell growth, proliferation, migration and invasion. Further, Lnc-EPIC1 silencing induced significant apoptosis activation in colon cancer cells. Conversely, ectopic overexpression of Lnc-EPIC1 augmented colon cancer cell growth, proliferation, migration and invasion. RNA-immunoprecipitation and RNA pull-down results confirmed that Lnc-EPIC1 directly binds MYC protein in colon cancer cells. MYC target proteins, including cyclin A, cyclin D and CDK9, were downregulated with Lnc-EPIC1 silencing, but upregulated after Lnc-EPIC1 overexpression in colon cancer cells. Further Lnc-EPIC1 silencing or overexpression failed to alter functions of MYC-knockout colon cancer cells. Collectively, overexpressed Lnc-EPIC1 is important for the progression of human colon cancer cells.

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“…As proliferation inhibition and cell cycle arrest can induce cell apoptosis in colon cancer cells 15,31,32 , we tested whether A1874 can provoke cell death and apoptosis. Trypan blue staining assay results, Fig.…”

Section: A1874 Induces Apoptosis Activation In Colon Cancer Cellsmentioning

confidence: 99%

The therapeutic effect of the BRD4-degrading PROTAC A1874 in human colon cancer cells

Qin

Jin

et al. 2020

Cell Death Dis

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A1874 is a novel BRD4-degrading proteolysis targeting chimera (PROTAC). In primary colon cancer cells and established HCT116 cells, A1874 potently inhibited cell viability, proliferation, cell cycle progression, as well as cell migration and invasion. The BRD4-degrading PROTAC was able to induce caspase and apoptosis activation in colon cancer cells. Furthermore, A1874-induced degradation of BRD4 protein and downregulated BRD-dependent genes (c-Myc, Bcl-2, and cyclin D1) in colon cancer cells. Significantly, A1874-induced anti-colon cancer cell activity was more potent than the known BRD4 inhibitors (JQ1, CPI203, and I-BET151). In BRD4-knockout colon cancer cells A1874 remained cytotoxic, indicating the existence of BRD4-independent mechanisms. In addition to BRD4 degradation, A1874 cytotoxicity in colon cancer cells was also associated with p53 protein stabilization and reactive oxygen species production. Importantly, the antioxidant N-acetyl-cysteine and the p53 inhibitor pifithrin-α attenuated A1874-induced cell death and apoptosis in colon cancer cells. In vivo, A1874 oral administration potently inhibited colon cancer xenograft growth in severe combined immuno-deficient mice. BRD4 degradation and p53 protein elevation, as well as apoptosis induction and oxidative stress were detected in A1874-treated colon cancer tissues. Together, A1874 inhibits colon cancer cell growth through both BRD4-dependent and -independent mechanisms.

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The novel HDAC inhibitor AR-42-induced anti-colon cancer cell activity is associated with ceramide production

Cited by 15 publications

References 25 publications

Target deconvolution of HDAC pharmacopoeia highlights MBLAC2 as common off-target

Target deconvolution of HDAC pharmacopoeia highlights MBLAC2 as common off-target

Targeting LncRNA EPIC1 to inhibit human colon cancer cell progression

The therapeutic effect of the BRD4-degrading PROTAC A1874 in human colon cancer cells

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