Cuprous oxide nanoparticle-inhibited melanoma progress by targeting melanoma stem cells

International Journal of Nanomedicine, Apr 2017

Cuprous oxide nanoparticle-inhibited melanoma progress by targeting melanoma stem cells Bin Yu,1,2,* Ye Wang,3,* Xinlu Yu,1,* Hongxia Zhang,1 Ji Zhu,4 Chen Wang,1 Fei Chen,1 Changcheng Liu,1 Jingqiang Wang,2 Haiying Zhu1 1Department of Cell Biology, Second Military Medical University, 2State Key Laboratory of Genetic Engineering and Collaborative Innovation Center of Genetics and Development, Ministry of Education Key Laboratory of Contemporary Anthropology, Department of Genetics and Development, School of Life Sciences, Fudan University, 3Department of Urinary Surgery, 4Department of Plastic Surgery, Changhai Hospital, Second Military Medical University, Shanghai, People’s Republic of China*These authors contributed equally to this work Abstract: Metal and its oxide nanoparticles have been showed the potential of antitumor therapy. Our previous studies demonstrated that cuprous oxide nanoparticles (CONPs) not only selectively induce apoptosis of tumor cells in vitro but also inhibit the growth and metastasis of melanoma by targeting mitochondria with little hepatic and renal toxicities in mice. As a further study, our current research revealed that CONPs induced apoptosis of human melanoma stem cells (CD271+/high cells) in A375 and WM266-4 melanoma cell lines and could significantly suppress the expression of MITF, SOX10 and CD271 involved in the stemness maintenance and tumorigenesis of melanoma stem cells. CD271+/high cells could accumulate more CONPs than CD271-/low through clathrin-mediated endocytosis. In addition, lower dosage of CONPs exhibited good anti-melanoma effect by decreasing the cell viability, stemness and tumorigenesis of A375 and WM266-4 cells through reducing the expression of SOX10, MITF, CD271 and genes in MAPK pathway involved in tumor progression. Finally, CONPs obviously suppressed the growth of human melanoma in tumor-bearing nonobese diabetic-severe combined immunodeficiency (NOD-SCID) mice, accompanied with tumors structural necrosis and fibrosis remarkably and decreased expression of CD271, SOX10 and MITF. These results above proved the effectiveness of CONPs in inhibiting melanoma progress through multiple pathways, especially through targeting melanoma stem cells.Keywords: cuprous oxide nanoparticles, CONPs, melanoma, cancer stem cells, A375 cell line, WM266-4 cell line, MITF, SOX10, clathrin-mediated endo­cytosis

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Cuprous oxide nanoparticle-inhibited melanoma progress by targeting melanoma stem cells

International Journal of Nanomedicine cuprous oxide nanoparticle-inhibited melanoma progress by targeting melanoma stem cells Bin Yu 1 2 3 5 6 Ye Wang 0 1 5 6 Xinlu 1 5 6 hongxia Zhang 1 3 5 6 0 Department of Urinary surgery 1 Jingqiang Wang 2 state Key laboratory of genetic engineering and collaborative Innovation center of genetics and Development, Ministry of education Key l aboratory of contemporary anthropology, Department of g enetics and Development, school of life sciences, Fudan University 3 Department of cell Biology, second Military Medical University 4 Department of Plastic surgery, changhai hospital, second Military Medical University , shanghai, People's republic of china 5 WM266-4 cell line , MITF, SOX10, clathrin-mediated endocytosis 6 haiying Zhu Department of cell Biology, second Military Medical University , 800, Xiangyin rd, shanghai 200433, People's republic of china Tel Recent studies have shown that metal and metal oxide have a potential function in antitumor therapy. Our previous studies demonstrated that cuprous oxide nanoparticles (CONPs) not only selectively induce apoptosis of tumor cells in vitro but also inhibit the growth and metastasis of melanoma by targeting mitochondria with little hepatic and renal toxicities in mice. As a further study, our current research revealed that CONPs induced apoptosis of human melanoma stem cells (CD271+/high cells) in A375 and WM266-4 melanoma cell lines and could significantly suppress the expression of MITF, SOX10 and CD271 involved in the stemness maintenance and tumorigenesis of melanoma stem cells. CD271+/high cells could accumulate more CONPs than CD271-/low through clathrin-mediated endocytosis. In addition, lower dosage of CONPs exhibited good anti-melanoma effect by decreasing the cell viability, stemness and tumorigenesis of A375 and WM266-4 cells through reducing the expression of SOX10, MITF, CD271 and genes in MAPK pathway involved in tumor progression. Finally, CONPs obviously suppressed the growth of human melanoma in tumor-bearing nonobese diabetic-severe combined immunodeficiency (NOD-SCID) mice, accompanied with tumors structural necrosis and fibrosis remarkably and decreased expression of CD271, SOX10 and MITF. These results above proved the effectiveness of CONPs in inhibiting melanoma progress through multiple pathways, especially through targeting melanoma stem cells. cuprous oxide nanoparticles; CONPs; melanoma; cancer stem cells; A375 cell line - a o l n w o d e n i c i d e m o n a N f o l a n r u o J l a n o it a n r e t n I open access to scientific and medical research correspondence: Jingqiang Wang state Key laboratory of genetic engineering and collaborative Innovation center of genetics and Development, Ministry of education Key laboratory of contemporary anthropology, Department of genetics and Development, school of life sciences, room e201-7, life sciences Building, 2005 songhu road, Jiangwan campus of Fudan University, shanghai 200438, People’s republic of china Tel +86 21 5163 0733 email Introduction Melanoma is highly aggressive cancer and the most lethal type of skin cancers with high metastatic potential, leaving untreated patients with a median survival of 12 months.1,2 Because melanoma has strong resistance to conventional therapies, such as surgical interventions, radiation, and cytotoxic chemotherapies, developing new medicine and therapy tends to be very important in melanoma therapy.3–6 Nano medicines have been emerging as one of the new treatment options.7 Many nano medicines such as gold nanoparticles, metallic multi-segments, silicon nanowire, iron core-gold shell nanoparticles, chitosan nanoparticles, and gold nanorods have been designed for tumor therapy.8–11 As a new member of potential antitumor drugs, cuprous oxide nanoparticles (CONPs) have been proven not only to induce apoptosis of tumor cells selectively in vitro but also to inhibit the growth and metastasis of melanoma by targeting mitochondria with little hepatic and renal toxicities in mice.12,13 In the meantime, a lot of studies focusing on the biological properties of melanoma provided more strategies for finding or designing new drugs and therapies.14 It is well known that cancer stem cells (CSCs) are considered to be the cause of tumor initiation, metastasis and recurrence and be responsible for the failure of chemotherapy and radiotherapy. Therefore, isolation and identification of CSCs is crucial for facilitating monitor, therapy or prevention of cancer.15–18 In recent research, lots of biomarkers including ABCB5 (ATP-binding cassette),19,20 NGFR (nerve growth factor receptor, CD271)21 and ALDH (aldehyde dehydrogenase)22 were used to identify melanoma stem cells. However, it should be noted that CD271-positive cells were proven to be “genuine cancer stem cells” by Boiko et al21 and Civenni.23 After that, there were a lot of studies supporting that the CD271 positive cells could drive melanoma initiation, progression, im (...truncated)


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Bin Yu, Ye Wang, Xinlu Yu, Hongxia Zhang, Ji Zhu, Chen Wang, Fei Chen, Changcheng Liu, Jingqiang Wang, Haiying Zhu. Cuprous oxide nanoparticle-inhibited melanoma progress by targeting melanoma stem cells, International Journal of Nanomedicine, 2017, pp. 2553-2567, DOI: 10.2147/IJN.S130753