title: Detention of copper by sulfur nanoparticles inhibits the proliferation of A375 malignant melanoma and MCF-7 breast cancer cells.
abstract: Selective induction of cell death or growth inhibition of cancer cells is the future of chemotherapy. Clinical trials have found that cancer tissues are enriched with copper. Based on this finding, many copper-containing compounds and complexes have been designed to "copper" cancer cells using copper as bait. However, recent studies have demonstrated that copper boosts tumor development, and copper deprivation from serum was shown to effectively inhibit the promotion of cancer. Mechanistically, copper is an essential cofactor for mitogen-activated protein kinase (MAPK)/extracellular activating kinase (ERK) kinase (MEK), a central molecule in the BRAF/MEK/ERK pathway. Therefore, depleting copper from cancer cells by directly sequestering copper has a wider field for research and potential for combination therapy. Based on the affinity between sulfur and copper, we therefore designed sulfur nanoparticles (Nano-S) that detain copper, achieving tumor growth restriction. We found that spherical Nano-S could effectively bind copper and form a tighter surficial structure. Moreover, this Nano-S detention of copper effectively inhibited the proliferation of A375 melanoma and MCF-7 breast cancer cells with minimum toxicity to normal cells. Mechanistic studies revealed that Nano-S triggered inactivation of the MEK-ERK pathway followed by inhibition of the proliferation of the A375 and MCF-7 cells. In addition, lower Nano-S concentrations and shorter exposure stimulated the expression of a copper transporter as compensation, which further increased the cellular uptake and anticancer activities of cisplatin. Collectively, our results highlight the potential of Nano-S as an anticancer agent or adjuvant through its detention of copper.
authors.affiliation: Department of Chemistry, Jinan University, Guangzhou, China.
authors.forename: Hao
authors.initials: H
authors.lastname: Liu
authors.affiliation: Institute of Hematology, Jinan University, Guangzhou, China.
authors.forename: Yikai
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: School of Life Sciences, The Chinese University of Hong Kong, Hong Kong, China.
authors.forename: Shanyuan
authors.initials: S
authors.lastname: Zheng
authors.affiliation: First Affiliated Hospital, Jinan University, Guangzhou, China.
authors.forename: Zeping
authors.initials: Z
authors.lastname: Weng
authors.affiliation: First Affiliated Hospital, Jinan University, Guangzhou, China.
authors.forename: Jun
authors.initials: J
authors.lastname: Ma
authors.affiliation: Institute of Hematology, Jinan University, Guangzhou, China; First Affiliated Hospital, Jinan University, Guangzhou, China; Key Laboratory for Regenerative Medicine of Ministry of Education, Jinan University, Guangzhou, 510632, China.
authors.forename: Yangqiu
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of Chemistry, Jinan University, Guangzhou, China.
authors.forename: Xinyuan
authors.initials: X
authors.lastname: Xie
authors.affiliation: Department of Chemistry, Jinan University, Guangzhou, China. Electronic address: tzhwj@jnu.edu.cn.
authors.forename: Wenjie
authors.initials: W
authors.lastname: Zheng
mesh_terms: D000970:Antineoplastic Agents / Q000008:administration & dosage; D017209:Apoptosis / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects*; D002945:Cisplatin / Q000008:administration & dosage; D003300:Copper / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D006801:Humans; D061986:MCF-7 Cells; D053758:Nanoparticles / Q000008:administration & dosage*; D009374:Neoplasms, Experimental / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D013455:Sulfur / Q000008:administration & dosage*; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; D013455:Sulfur; D003300:Copper; D002945:Cisplatin
keywords: Cancer chemotherapy; Combination therapy; Copper; Signal transduction; Sulfur nanoparticles