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Auranofin and ICG-001 Emerge Synergistic Anti-tumor Effect on Canine Breast Cancer by Inducing Apoptosis via Mitochondrial Pathway.

ABSTRACT: Canine breast cancer (CBC) is the most common spontaneous tumor in intact female dogs, especially in developing countries. The effective anti-tumor agents or therapies for the clinical treatment of CBC are still in need. Auranofin (AF) is a gold complex that has been attested by FDA for treating human rheumatism, which has been found as a great anti-tumor agent in recent years. ICG-001 is a small molecule inhibitor of Wnt/β-catenin pathway. In the present study, we demonstrated that a combination of AF and ICG-001 could synergistically suppress the proliferation of CBC in vitro and in vivo. Moreover, the synergistical effect was related with apoptosis caused by mitochondrial damage and ROS production. In conclusion, combination of AF and ICG-001 could synergistically suppress the growth of CBC in vitro and in vivo by leading apoptosis via mitochondrial signaling pathway and might provide a novel potential choice for the clinical treatment of CBC.

SUBMITTER: Lin Z

PROVIDER: S-EPMC8714754 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Combination of Auranofin and ICG-001 Suppress the Proliferation and Metastasis of Colon Cancer.

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| S-EPMC8651623 | biostudies-literature

ICG-001 affects DRP1 activity and ER stress correlative with its anti-proliferative effect.

Project description:Mitochondria form a highly dynamic network driven by opposing scission and fusion events. DRP1 is an essential modulator of mitochondrial fission and dynamics within mammalian cells. Its fission activity is regulated by posttranslational modifications such as activating phosphorylation at serine 616. DRP1 activity has recently been implicated as being dysregulated in numerous human disorders such as cancer and neurodegenerative diseases. Here we describe the development of a cell-based screening assay to detect DRP1 activation. We utilized this to undertake focused compound library screening and identified potent modulators that affected DRP1 activity including ICG-001, which is described as WNT/?-catenin signaling inhibitor. Our findings elucidate novel details about ICG-001's mechanism of action (MOA) in mediating anti-proliferative activity. We show ICG-001 both inhibits mitochondrial fission and activates an early endoplasmic reticulum (ER) stress response to induce cell death in susceptible colorectal cancer cell lines.

| S-EPMC5739772 | biostudies-literature

Auranofin induces apoptosis by ROS-mediated ER stress and mitochondrial dysfunction and displayed synergistic lethality with piperlongumine in gastric cancer.

Project description:Gastric cancer (GC) is one of the leading causes of cancer mortality in the world. In addressing the need of treatments for relapsed disease, we report the identification of an existing U.S. Food and Drug Administration-approved small-molecule drug to repurpose for GC treatment. Auranofin (AF), clinically used to treat rheumatic arthritis, but it exhibited preclinical efficacy in GC cells. By increasing intracellular reactive oxygen species (ROS) levels, AF induces a lethal endoplasmic reticulum stress response and mitochondrial dysfunction in cultured GC cells. Blockage of ROS production reversed AF-induced ER stress and mitochondrial pathways activation as well as apoptosis. In addition, AF displays synergistic lethality with an ROS-generating agent piperlongumine, which is a natural product isolated from the long pepper Piper longum L. Taken together, this work provides a novel anticancer candidate for the treatment of gastric cancer. More importantly, it reveals that increased ROS generation might be an effective strategy in treating human gastric cancer.

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RNA-seq in HSJD-DIPG-007 cells treated with JQ1, ICG-001, JQ1 and ICG-001 and DMSO as control.

Project description:This study aims to characterize gene expression changes upon treatment with JQ1, ICG-001, and combined treatment. The general goal is to identify the mechanism for high efficacy of combinatorial treatment of BET and CBP inhibition in DIPG cells.

2020-08-01 | E-MTAB-8243 | biostudies-arrayexpress

Expression data from AsPC1 cells treated with ICG-001

2014-07-15 | GSE57728 | GEO

Expression data from AsPC1 cells treated with ICG-001

Project description:The CREB binding protein inhibitor ICG-001 suppresses pancreatic cancer growth We used microarrays to detail global gene expression changes in the pancreatic cancer cell line AsPC1 following treatment with ICG-001 or siRNA-mediated knockdown of CTNNB1 (beta-catenin) AsPC1 cells were treated with 10uM ICG-001 or vehicle control (DMSO) for either 6 hours or 24 hours. AsPC-1 cells were also separately transfected with 20nM control siRNA or CTNNB1 siRNA for 48 hours. RNA was extracted at these time points for hybridization to Affymetrix microarrays

| S-ECPF-GEOD-57728 | biostudies-other

ICG-001 Exerts Potent Anticancer Activity Against Uveal Melanoma Cells.

Project description:PurposeUveal melanoma (UM) is uniformly refractory to all available systemic chemotherapies, thus creating an urgent need for novel therapeutics. In this study, we investigated the sensitivity of UM cells to ICG-001, a small molecule reported to suppress the Wnt/β-catenin-mediated transcriptional program.MethodsWe used a panel of UM cell lines to examine the effects of ICG-001 on cellular proliferation, migration, and gene expression. In vivo efficacy of ICG-001 was evaluated in a UM xenograft model.ResultsICG-001 exerted strong antiproliferative activity against UM cells, leading to cell cycle arrest, apoptosis, and inhibition of migration. Global gene expression profiling revealed strong suppression of genes associated with cell cycle proliferation, DNA replication, and G1/S transition. Gene set enrichment analysis revealed that ICG-001 suppressed Wnt, mTOR, and MAPK signaling. Strikingly, ICG-001 suppressed the expression of genes associated with UM aggressiveness, including CDH1, CITED1, EMP1, EMP3, SDCBP, and SPARC. Notably, the transcriptomic footprint of ICG-001, when applied to a UM patient dataset, was associated with better clinical outcome. Lastly, ICG-001 exerted anticancer activity against a UM tumor xenograft in mice.ConclusionsUsing in vitro and in vivo experiments, we demonstrate that ICG-001 has strong anticancer activity against UM cells and suppresses transcriptional programs critical for the cancer cell. Our results suggest that ICG-001 holds promise and should be examined further as a novel therapeutic agent for UM.

| S-EPMC5769500 | biostudies-literature

Expression data from AsPC1 cells treated with ICG-001

2014-07-15 | E-GEOD-57728 | biostudies-arrayexpress

The CREB-binding protein inhibitor ICG-001 suppresses pancreatic cancer growth.

Project description:Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal cancer due in part to a lack of highly robust cytotoxic or molecular-based therapies. Recent studies investigating ligand-mediated Wnt/?-catenin signaling have highlighted its importance in pancreatic cancer initiation and progression, as well as its potential as a therapeutic target in PDAC. The small-molecule ICG-001 binds cAMP-responsive element binding (CREB)-binding protein (CBP) to disrupt its interaction with ?-catenin and inhibit CBP function as a coactivator of Wnt/?-catenin-mediated transcription. Given its ability to inhibit Wnt/?-catenin-mediated transcription in vitro and in vivo, as well as its efficacy in preclinical models of colorectal cancer and other Wnt-driven diseases, we examined ICG-001 and its potential role as a therapeutic in PDAC. ICG-001 alone significantly inhibited anchorage-dependent and -independent growth of multiple PDAC lines, and augmented in vitro growth inhibition when used in combination with gemcitabine. ICG-001 had only variable modest effects on PDAC apoptosis and instead mediated PDAC growth inhibition primarily through robust induction of G? cell-cycle arrest. These effects, however, seemed decoupled from its inhibition of Wnt/?-catenin-mediated transcription. DNA microarrays performed on PDAC cells in the context of ICG-001 treatment revealed ICG-001 altered the expression of several genes with well-established roles in DNA replication and cell-cycle progression, including direct actions on SKP2 and CDKN1A. ICG-001 also significantly prolonged survival in an in vivo orthotopic xenograft model of PDAC, indicating ICG-001 or derived compounds that disrupt CBP activity are potentially useful small-molecule therapeutics for pancreatic cancer.

| S-EPMC4188417 | biostudies-literature

Regulation of gene expression in uveal melanoma cells by ICG-001

Project description:We examined the effects of ICG-001 on gene expression in Mel202 uveal melanoma (UM) cells. ICG-001 exerted strong antiproliferative activity against UM cells, leading to cell cycle arrest, apoptosis, and inhibition of migration. Global gene expression profiling revealed strong suppression of genes associated with cell cycle proliferation, DNA replication, and G1/S transition. Gene set enrichment analysis revealed that ICG-001 suppressed Wnt, mTOR, and MAPK signaling. Strikingly, ICG-001 suppressed the expression of genes associated with UM aggressiveness, including CDH1, CITED1, EMP1, EMP3, SDCBP, and SPARC. Notably, the transcriptomic footprint of ICG-001, when applied to a UM patient dataset, was associated with better clinical outcome. Lastly, ICG-001 exerted anticancer activity against a UM tumor xenograft in mice.

2020-04-28 | GSE149417 | GEO

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