Antitumor effects of disulfiram/copper complex in the poorly-differentiated nasopharyngeal carcinoma cells via activating ClC-3 chloride channel

Xu, Xiao Yun; Xu, Jingkui; Zhao, Cheng; Hou, Xiuying; Li, Mengjia; Wang, Liwei; Chen, Lixin; Chen, Ye‐Hui; Zhu, Linyan; Yang, Haifeng

doi:10.1016/j.biopha.2019.109529

Cited by 19 publications

(15 citation statements)

References 33 publications

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“…Previously, two studies indicated that DSF/Cu induces NPC cell apoptosis by increasing chloride channel-3 protein expression, or by inducing ROS production and decreasing NF-KB-p65 expression [36,37]. These studies, together with our findings, indicate that DSF/Cu induces anti-NPC activity through a joint action of multiple pathways.…”

Section: Discussionsupporting

confidence: 84%

Disulfiram/Copper Induces Antitumor Activity against Both Nasopharyngeal Cancer Cells and Cancer-Associated Fibroblasts through ROS/MAPK and Ferroptosis Pathways

Chen

et al. 2020

Cancers

133

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Disulfiram/copper (DSF/Cu) is a promising antitumor reagent for clinical application due to its excellent anticancer activity and safety. However, the anticancer mechanism of DSF/Cu has not been fully elucidated. Our study showed that DSF/Cu strongly induced cytotoxic effects on both nasopharyngeal carcinoma (NPC) cells and α-smooth muscle actin (α-SMA)-positive fibroblasts. Fluorescence activated cell sorting (FACS) analysis further showed that DSF/Cu induced a higher late apoptosis rate in α-SMA-positive fibroblasts than in tumor cells, and DSF/Cu promoted apoptosis and necrosis by an aldehyde dehydrogenase (ALDH)-independent method. Furthermore, we found that the antitumor activity of DSF/Cu against NPC cells occurred through ROS/MAPK and p53-mediated ferroptosis pathways, and that the ROS scavenger N-acetyl-l-cysteine (NAC) could reverse the cellular and lipid ROS levels. In 5-8F xenografts, both TUNEL and immunohistochemical (IHC) analyses indicated that DSF/Cu could induce apoptosis and inactivate cancer-associated fibroblasts (CAFs) by inhibiting the expression of α-SMA. In addition, combined with cisplatin (CDDP), DSF/Cu was well tolerated in vivo and could significantly suppress the growth of NPC tissues. Our study demonstrated that DSF/Cu induced antitumor activity against both tumor cells, as well as CAFs and suggested that the use of DSF/Cu as an adjunctive therapy for NPC is worthy of consideration.

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Section: Discussionsupporting

confidence: 84%

Disulfiram/Copper Induces Antitumor Activity against Both Nasopharyngeal Cancer Cells and Cancer-Associated Fibroblasts through ROS/MAPK and Ferroptosis Pathways

Chen

et al. 2020

Cancers

133

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“…Many studies have demonstrated that DSF possesses copper-dependent anticancer activity and that copper greatly enhances the antitumor efficacy of DSF. 24 In fact, the IC 50 of DSF in several tumor types was decreased when combined with copper. 25 Further study is therefore warranted to determine whether the combination of DSF with copper is more efficient in triggering ferroptosis and LMP in GBM.…”

Section: Discussionmentioning

confidence: 98%

<p>Disulfiram, a Ferroptosis Inducer, Triggers Lysosomal Membrane Permeabilization by Up-Regulating ROS in Glioblastoma</p>

Qiu¹,

Zhang²,

Huang³

et al. 2020

OTT

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Introduction: Disulfiram (DSF), a drug used in the treatment of alcoholism since 1948, has been shown to have antitumor properties in various tumor types possibly due to the induction of a type cell death, ferroptosis, and the sensitization of cells to chemo-and radiotherapy. In this study, we explored the antitumor properties of DSF in glioblastoma (GBM) and investigated the underlying molecular mechanisms. Methods: GBM cell lines U251 and LN229 were treated with DSF to assess cytotoxicity and activity of the molecule in vitro. Response of cells to treatment was examined using cell viability, flow cytometry, LDH release assay, immunofluorescence and Western blot analysis. Results: DSF inhibited cell growth of GBM U251 and LN229 cell lines in vitro in a concentration-dependent manner. Flow cytometry demonstrated that DSF caused G0-G1 growth arrest. DSF treatment led to increased ROS and lipid peroxidation levels relative to controls indicating the involvement of ferroptosis. Furthermore, DSF triggered lysosomal membrane permeabilization (LMP), a critical mechanism promoting cell death, in a ROSdependent manner. Finally, DSF enhanced radiosensitivity of U251 and LN229 cells. Discussion: Our findings indicated that DSF induced ferroptosis and LMP and enhanced the radiosensitivity of GBM cells. Therefore, DSF might have efficient antitumor activity in the treatment of human GBM.

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“…Yiqiu Li et al reported a DSF/Cu combination to induce anti-NPC activity through a joint action of multiple apoptosis pathways, such as an increasing chloride channel-3 protein expression, inducing ROS production, and decreasing NF-KB-p65 expression [86], and inhibiting the expression of α-SMA in cancer-associated fibroblasts (CAFs) [87]. In vivo, DSF/Cu combined with cisplatin (CDDP) therapy was well tolerated and could significantly suppress the growth of nasopharyngeal Dithiocarbamates are a known class of copper chelating agents that exhibit significant antitumor activity in vitro against various tumor cell lines [79].…”

Section: S/s-donor Ligandsmentioning

confidence: 99%

Copper Coordination Compounds as Biologically Active Agents

Krasnovskaya

Naumov

Guk

et al. 2020

IJMS

130

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Copper-containing coordination compounds attract wide attention due to the redox activity and biogenicity of copper ions, providing multiple pathways of biological activity. The pharmacological properties of metal complexes can be fine-tuned by varying the nature of the ligand and donor atoms. Copper-containing coordination compounds are effective antitumor agents, constituting a less expensive and safer alternative to classical platinum-containing chemotherapy, and are also effective as antimicrobial, antituberculosis, antimalarial, antifugal, and anti-inflammatory drugs. 64Cu-labeled coordination compounds are promising PET imaging agents for diagnosing malignant pathologies, including head and neck cancer, as well as the hallmark of Alzheimer’s disease amyloid-β (Aβ). In this review article, we summarize different strategies for possible use of coordination compounds in the treatment and diagnosis of various diseases, and also various studies of the mechanisms of antitumor and antimicrobial action.

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Antitumor effects of disulfiram/copper complex in the poorly-differentiated nasopharyngeal carcinoma cells via activating ClC-3 chloride channel

Cited by 19 publications

References 33 publications

Disulfiram/Copper Induces Antitumor Activity against Both Nasopharyngeal Cancer Cells and Cancer-Associated Fibroblasts through ROS/MAPK and Ferroptosis Pathways

Disulfiram/Copper Induces Antitumor Activity against Both Nasopharyngeal Cancer Cells and Cancer-Associated Fibroblasts through ROS/MAPK and Ferroptosis Pathways

<p>Disulfiram, a Ferroptosis Inducer, Triggers Lysosomal Membrane Permeabilization by Up-Regulating ROS in Glioblastoma</p>

Copper Coordination Compounds as Biologically Active Agents

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