Endothelial Antioxidant-1: a Key Mediator of Copper-dependent Wound Healing in vivo

Das, Archita; Varadarajan, Sudhahar; Chen, Gin‐Fu; Kim, Ha Won; Youn, Seock Won; Finney, Lydia; Vogt, Stefan; Yang, Jay; Kweon, Junghun; Surenkhuu, Bayasgalan; Ushio‐Fukai, Masuko; Fukai, Tohru

doi:10.1038/srep33783

Cited by 68 publications

(56 citation statements)

References 46 publications

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“…CCS is also required for coppermediated activation of HIF-1a to promote VEGF expression (18). ATOX1 has a possible role in metastasis: It promotes inflammatory neovascularization (19), wound closure (20), and breast cancer cell migration (21). Altogether, this evidence demonstrates that copper chaperone proteins, ATOX1 and CCS, are attractive targets for anti-cancer therapy.…”

Section: Introductionmentioning

confidence: 99%

Inhibition of Copper Transport Induces Apoptosis in Triple-Negative Breast Cancer Cells and Suppresses Tumor Angiogenesis

Karginova

Weekley

Raoul

et al. 2019

Molecular Cancer Therapeutics

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Treatment of advanced breast cancer remains challenging. Copper and some of the copper-dependent proteins are emerging therapeutic targets because they are essential for cell proliferation and survival, and have been shown to stimulate angiogenesis and metastasis. Here, we show that DCAC50, a recently developed small-molecule inhibitor of the intracellular copper chaperones, ATOX1 and CCS, reduces cell proliferation and elevates oxidative stress, triggering apoptosis in a panel of triple-negative breast cancer (TNBC) cells. Inhibition of ATOX1 activity with DCAC50 disrupts copper homeostasis, leading to increased copper levels, altered spatial copper redistribution, and accumula-tion of ATP7B to the cellular perinuclear region. The extent and impact of this disruption to copper homeostasis vary across cell lines and correlate with cellular baseline copper and glutathione levels. Ultimately, treatment with DCAC50 attenuates tumor growth and suppresses angiogenesis in a xenograft mouse model, and prevents endothelial cell network formation in vitro. Co-treatment with paclitaxel and DCAC50 enhances cytotoxicity in TNBC and results in favorable dose reduction of both drugs. These data demonstrate that inhibition of intracellular copper transport targets tumor cells and the tumor microenvironment, and is a promising approach to treat breast cancer.

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Section: Introductionmentioning

confidence: 99%

Inhibition of Copper Transport Induces Apoptosis in Triple-Negative Breast Cancer Cells and Suppresses Tumor Angiogenesis

Karginova

Weekley

Raoul

et al. 2019

Molecular Cancer Therapeutics

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“…We reasoned that overexpressing exogenous ATOX1 under generic CMV promoter should allow IGROV-CP20 cells to circumvent inhibitory impact of Tranilast on transcription of endogenous ATOX1. Thus the cells were transfected with ATOX1-FLAG plasmid (42) and incubated with cisplatin alone or in combination with Tranilast. Initially we analyzed the impact of ATOX1 overexpression on Pt-dependent trafficking of ATP7B in Tranilast-treated cells.…”

Section: Tranilast Affects Atp7b Trafficking In Pt-resistant Tumor Cementioning

confidence: 99%

“…As mentioned above ATOX1 deficit inhibits ATP7B trafficking and hence its ability to sequester/efflux toxic Pt. Moreover, ATOX1 activity stimulates angiogenesis (42). Considering that vascularization of tumors support their survival and growth, Tranilast might inhibit these processes counteracting ATOX1-mediated angiogenesis.…”

Section: Resistance Of Tumors To Chemotherapy Represents An Importantmentioning

confidence: 99%

Synthetic lethality screening identifies FDA-approved drugs that overcome ATP7B-mediated tolerance of tumor cells to cisplatin

Mariniello¹,

Petruzzelli²,

Wanderlingh³

et al. 2019

Preprint

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Resistance of tumors to chemotherapy represents an important challenge in the modern oncology. Although platinum (Pt)-based drugs demonstrated excellent therapeutic potential their effectiveness in a wide range of tumors is limited by the development of resistance mechanisms. One of these mechanisms includes increased cisplatin sequestration/efflux by copper-transporting ATPase, ATP7B. In fact, ATP7B expression has been identified as a hallmark of chemotherapy-resistant tumors. However, targeting the ATP7B for reduction of Pt-tolerance in tumors represents a serious risk because suppression of ATP7B might compromise copper homeostasis like it happens in Wilson disease.To circumvent ATP7B-mediated Pt tolerance we employed a high-throughput screening (HTS) of FDA/EMA-approved drug library to discover new therapeutic molecules that promote cisplatin toxicity in resistant ovarian carcinoma IGROV-CP20 cell line. Through a synthetic lethality approach, three hits (Tranilast, Telmisartan and Amphotericin B) were detected and validated for their ability to reduce cisplatin resistance. All 3 drugs induced DNA damage and inhibited ATP7B trafficking in a tumor-specific manner. RNAseq analysis revealed Tranilast and Amphotericin B to affect expression of genes operating in several pathways that confer tolerance to cisplatin. In the case of Tranilast, these included key molecular players operating in the distribution of copper and platinum to different intracellular compartments. In particular, Tranilast was found to suppress ATOX1 and, as a consequence, ATOX1-mediated trafficking of ATP7B in response to cisplatin.Considering well-known safety profiles and tolerability of Tranilast, Telmisartan and Amphotericin B these drugs emerge as attractive candidates, which might be used for rapid development of new therapeutic strategies to overcome resistance of tumors to Pt-based chemotherapy.

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“…够调控NADPH氧化酶P47phox的表达, 促进内皮细胞中活性氧簇ROS水平升高以及炎症细胞浸润, 从而诱导新血管的生成 [28] . 在小鼠皮肤伤口愈合模型中, 小鼠受伤时细胞中铜离子含量和细胞核中Atox1的表达水平均上升 [29] , Atox1稳定敲低后伤口愈合速率减慢, 张美琪等: 铜转运蛋白与癌症的研究进展进作用 [33,34] . .…”

Section: 序列在不同物种中具有高度保守性该序列存在于32unclassified

Recent advances in copper chaperone and cancer

Zhang¹,

Chen²,

Wang³

2018

Sci. Sin.-Chim

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Copper is a redox-active transition metal essential for most living organisms and serves as a catalytic cofactor for enzymes that function in antioxidant defence, iron homeostasis, cellular respiration and a variety of biochemical processes. However, intracellular free copper must be strictly limited because of its potential toxic side effects. Copper dyshomeostasis is involved in the pathogenesis and progression of diseases including cancer and neurodegenerative diseases. The uncontrolled accumulation of copper could lead to increased oxidative stress and inappropriate binding to macromolecules. Most cells evolve complex systems of copper regulation and trafficking to satisfy the cellular copper requirements and simultaneously minimize the potential toxicity. This review presents the importance of copper transporter Ctr1, copper chaperone CCS, Atox1 and COX17 for the maintenance of copper ion balance in cells. Moreover, we discuss recent highlights in the development of copper chelators for the treatment of cancer. Finally, we introduce the development of small molecules that alter copper homeostasis by inhibiting copper chaperones.

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Endothelial Antioxidant-1: a Key Mediator of Copper-dependent Wound Healing in vivo

Cited by 68 publications

References 46 publications

Inhibition of Copper Transport Induces Apoptosis in Triple-Negative Breast Cancer Cells and Suppresses Tumor Angiogenesis

Inhibition of Copper Transport Induces Apoptosis in Triple-Negative Breast Cancer Cells and Suppresses Tumor Angiogenesis

Synthetic lethality screening identifies FDA-approved drugs that overcome ATP7B-mediated tolerance of tumor cells to cisplatin

Recent advances in copper chaperone and cancer

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