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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.

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| 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.

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| S-EPMC4188417 | biostudies-literature

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Project description:Colorectal cancer (CRC) remains the third most frequently diagnosed cancer in the United States. The current treatment regimens for CRC include surgery followed by 5FU-based chemotherapy. Cancer stem-like cells (CSCs) have been implicated in 5FU-mediated chemoresistance, which leads to poor prognosis. In this study, we used metformin along with ICG-001, a Wnt signaling inhibitor, to abrogate CSC-mediated chemoresistance in CRC. We observed that 5FU-resistant (5FUR) CRC cells exhibited increased expression of CSC markers and enhanced spheroid formation. Genome-wide transcriptomic profiling analysis revealed that Wnt signaling, colorectal cancer metastasis signaling, etc., were enriched in 5FUR CRC cells. Accordingly, selective targeting of Wnt signaling using ICG-001 along with metformin abrogated CSC-mediated chemoresistance by decreasing the expression of CSC markers and promoting autophagy and apoptosis in a synergistic manner. We also observed that metformin and ICG-001 exhibited anti-tumor activity in CRC patient-derived tumor organoids. In conclusion, our study highlights that metformin and ICG-001 act synergistically and can be used as part of a therapeutic strategy to overcome 5FU-mediated therapeutic resistance in CRC.

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