Detention of copper by sulfur nanoparticles inhibits the proliferation of A375 malignant melanoma and MCF-7 breast cancer cells

• Published in: Biochemical and biophysical research communications 2016-09, Vol.477 (4), p.1031-1037
• Main Authors: Liu, Hao, Zhang, Yikai, Zheng, Shanyuan, Weng, Zeping, Ma, Jun, Li, Yangqiu, Xie, Xinyuan, Zheng, Wenjie
• Format: Article
• Language: English
• Subjects: 60 APPLIED LIFE SCIENCES; adjuvants; ANIMAL TISSUES; antineoplastic activity; Antineoplastic Agents - administration & dosage; APOPTOSIS; Apoptosis - drug effects; blood serum; breast neoplasms; Cancer chemotherapy; cell death; Cell Proliferation - drug effects; CHEMOTHERAPY; cisplatin; Cisplatin - administration & dosage; CLINICAL TRIALS; Combination therapy; CONCENTRATION RATIO; COPPER; Copper - metabolism; Dose-Response Relationship, Drug; Drug Synergism; drug therapy; growth retardation; Humans; INHIBITION; MAMMARY GLANDS; MCF-7 Cells; melanoma; MELANOMAS; mitogen-activated protein kinase; MITOGENS; MITOSIS; MOLECULES; NANOPARTICLES; Nanoparticles - administration & dosage; neoplasm cells; Neoplasms, Experimental - drug therapy; Neoplasms, Experimental - metabolism; Neoplasms, Experimental - pathology; PROTEINS; Signal transduction; SPHERICAL CONFIGURATION; SULFUR; Sulfur - administration & dosage; Sulfur nanoparticles; TOXICITY; Treatment Outcome; UPTAKE
• ISSN: 0006-291X; 1090-2104
• DOI: 10.1016/j.bbrc.2016.07.026

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. [Display omitted] •Nano-S selectively inhibited the mitosis of A375 and MCF-7 cells by depleting copper.•Nano-S inactivated MEK/ERK pathway through the detention of copper.•Nano-S improved the cellular uptake and anticancer activities of cisplatin.