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Antitumor effects of disulfiram/copper complex in the poorly-differentiated nasopharyngeal carcinoma cells via activating ClC-3 chloride channel.
Biomed Pharmacother 2019; 120:109529BP

Abstract

The enhancement of the anticancer activity by disulfiram (DSF) chelated with copper (DSF/Cu2+) has been investigated recently, while the underlying molecular mechanisms still need to be fully elucidated. Chloride channel-3 (ClC-3) is over-expressed in a variety of cancers and involves multiple tumor biological events. However, whether the over-expression of ClC-3 in tumor cells affects the sensitivity of anti-tumor drugs remains unclear. Here, we showed that the involvement of ClC-3 chloride channel in the selective cytotoxicity of DSF/Cu2+ in the poorly-differentiated nasopharyngeal carcinoma. The EC50 of DSF alone and DSF/Cu2+ in activating the Cl- channel were 95.36 μM and 0.31 μM in the CNE-2Z cells, respectively. DSF/Cu2+ exhibited a positive correlation between the induction of the Cl- currents and the inhibition of cell proliferation. DSF/Cu2+ increased the ClC-3 protein expression and induced the cell apoptosis. Cl- channel blockers, NPPB and DIDS, and ClC-3 siRNA partially inhibited the cell apoptosis, and depleted the Cl- currents induced by DSF/Cu2+ in CNE-2Z cells. However, these effects could not be observed in the normal nasopharyngeal epithelium NP69-SV40 T cells. In vivo, the transplanted human nasopharyngeal carcinoma tumors size in the DSF/Cu2+ group decreased about 73.2% of those in the solvent control group. The chloride blockers partially inhibited the antitumor action of DSF/Cu2+. These data demonstrated that the selective cytotoxicity of DSF/Cu2+ may relate to its selective activation of ClC-3 Cl- channel pathways in CNE-2Z cells. ClC-3 Cl- channel can be viewed as a new and promising target for the treatment of nasopharyngeal carcinoma.

Authors+Show Affiliations

Department of Physiology, School of Medicine, Henan University, Kaifeng, 475000, China; Department of Physiology, School of Medicine, Jinan University, Guangzhou, 510632, China.Department of Physiology, School of Medicine, Jinan University, Guangzhou, 510632, China.Department of Pharmacology, School of Medicine, Jinan University, Guangzhou, 510632, China.Department of Physiology, School of Medicine, Jinan University, Guangzhou, 510632, China.Department of Pharmacology, School of Medicine, Jinan University, Guangzhou, 510632, China.Department of Physiology, School of Medicine, Jinan University, Guangzhou, 510632, China.Department of Pharmacology, School of Medicine, Jinan University, Guangzhou, 510632, China.Department of Urology, Guangzhou First People's Hospital, Guangzhou, 510180, China.Department of Physiology, School of Medicine, Jinan University, Guangzhou, 510632, China; Department of Pharmacology, School of Medicine, Jinan University, Guangzhou, 510632, China. Electronic address: tzhuly@jnu.edu.cn.Department of Pathology, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine (Guangdong Provincial Hospital of Chinese Medicine), Guangzhou, 510120, China. Electronic address: yang_hf@126.com.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

31606620

Citation

Xu, Xiao, et al. "Antitumor Effects of Disulfiram/copper Complex in the Poorly-differentiated Nasopharyngeal Carcinoma Cells Via Activating ClC-3 Chloride Channel." Biomedicine & Pharmacotherapy = Biomedecine & Pharmacotherapie, vol. 120, 2019, p. 109529.
Xu X, Xu J, Zhao C, et al. Antitumor effects of disulfiram/copper complex in the poorly-differentiated nasopharyngeal carcinoma cells via activating ClC-3 chloride channel. Biomed Pharmacother. 2019;120:109529.
Xu, X., Xu, J., Zhao, C., Hou, X., Li, M., Wang, L., ... Yang, H. (2019). Antitumor effects of disulfiram/copper complex in the poorly-differentiated nasopharyngeal carcinoma cells via activating ClC-3 chloride channel. Biomedicine & Pharmacotherapy = Biomedecine & Pharmacotherapie, 120, p. 109529. doi:10.1016/j.biopha.2019.109529.
Xu X, et al. Antitumor Effects of Disulfiram/copper Complex in the Poorly-differentiated Nasopharyngeal Carcinoma Cells Via Activating ClC-3 Chloride Channel. Biomed Pharmacother. 2019 Oct 10;120:109529. PubMed PMID: 31606620.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Antitumor effects of disulfiram/copper complex in the poorly-differentiated nasopharyngeal carcinoma cells via activating ClC-3 chloride channel. AU - Xu,Xiao, AU - Xu,Jingkui, AU - Zhao,Chongyu, AU - Hou,Xiuying, AU - Li,Mengjia, AU - Wang,Liwei, AU - Chen,Lixin, AU - Chen,Yehui, AU - Zhu,Linyan, AU - Yang,Haifeng, Y1 - 2019/10/10/ PY - 2019/07/20/received PY - 2019/09/30/revised PY - 2019/10/01/accepted PY - 2019/10/14/pubmed PY - 2019/10/14/medline PY - 2019/10/14/entrez KW - Anti-neoplasm KW - Apoptosis KW - Chloride channel KW - Copper KW - Disulfiram KW - Neoplasm SP - 109529 EP - 109529 JF - Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie JO - Biomed. Pharmacother. VL - 120 N2 - The enhancement of the anticancer activity by disulfiram (DSF) chelated with copper (DSF/Cu2+) has been investigated recently, while the underlying molecular mechanisms still need to be fully elucidated. Chloride channel-3 (ClC-3) is over-expressed in a variety of cancers and involves multiple tumor biological events. However, whether the over-expression of ClC-3 in tumor cells affects the sensitivity of anti-tumor drugs remains unclear. Here, we showed that the involvement of ClC-3 chloride channel in the selective cytotoxicity of DSF/Cu2+ in the poorly-differentiated nasopharyngeal carcinoma. The EC50 of DSF alone and DSF/Cu2+ in activating the Cl- channel were 95.36 μM and 0.31 μM in the CNE-2Z cells, respectively. DSF/Cu2+ exhibited a positive correlation between the induction of the Cl- currents and the inhibition of cell proliferation. DSF/Cu2+ increased the ClC-3 protein expression and induced the cell apoptosis. Cl- channel blockers, NPPB and DIDS, and ClC-3 siRNA partially inhibited the cell apoptosis, and depleted the Cl- currents induced by DSF/Cu2+ in CNE-2Z cells. However, these effects could not be observed in the normal nasopharyngeal epithelium NP69-SV40 T cells. In vivo, the transplanted human nasopharyngeal carcinoma tumors size in the DSF/Cu2+ group decreased about 73.2% of those in the solvent control group. The chloride blockers partially inhibited the antitumor action of DSF/Cu2+. These data demonstrated that the selective cytotoxicity of DSF/Cu2+ may relate to its selective activation of ClC-3 Cl- channel pathways in CNE-2Z cells. ClC-3 Cl- channel can be viewed as a new and promising target for the treatment of nasopharyngeal carcinoma. SN - 1950-6007 UR - https://www.unboundmedicine.com/medline/citation/31606620/Antitumor_effects_of_disulfiram/copper_complex_in_the_poorly-differentiated_nasopharyngeal_carcinoma_cells_via_activating_ClC-3_chloride_channel L2 - https://linkinghub.elsevier.com/retrieve/pii/S0753-3322(19)33552-8 DB - PRIME DP - Unbound Medicine ER -