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Open Access Anti-ganglioside GD2 monoclonal antibody synergizes with cisplatin to induce endoplasmic reticulum-associated apoptosis in osteosarcoma cells

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Cisplatin is an effective chemotherapeutic agent for osteosarcoma (OS) and has been shown to induce endoplasmic reticulum (ER) stress-associated apoptosis in human cancer cells. Ganglioside GD2-specific antibodies can inhibit tumor cell viability without involvement of the immune system. A recent study has shown that antiGD2 monoclonal antibody (mAb) 14G2a effectively inhibits the viability and invasiveness of human OS cells. In this study, we explored the effect of anti-GD2 mAb and cisplatin alone and in combination on ER stress-associated apoptosis in osteosarcoma cells. MG-63 and Saos-2 human OS cells were treated with cisplatin and/or an-GD2 mAb 14G2a for 48 hours. Cisplatin and 14G2a dose-dependently induced apoptosis in MG-63 and Saos-2 cells. They in combination induced 70%-77% of apoptosis in MG-63 cells and 79%-85% of apoptosis in Saos-2 cells, exhibiting a synergistic effect stronger than addition of their individual effects over the control level. Showing no significant effect on the expression of protein kinase RNA-like ER kinase (PERK), cisplatin and 14G2a exhibited a marked synergistic effect on inducing phosphorylation/activation of PERK, phosphorylation/inactivation of eukaryotic translation initiation factor 2α (eIF2α), expression of CHOP, in parallel to inducing the caspase-3 activity and apoptosis in MG-63 and Saos-2 cells. The effects were abolished by lentivirus-mediated knockdown of PERK. Particularly, PERK knockdown abolished 63% and 65% of the combined apoptotic effect of cisplatin and 14G2a on MG-63 and Saos-2 cells, respectively. In conclusion, this study provides the first evidence supporting that cisplatin and 14G2a synergize to induce ER stress-associated apoptosis in human OS cells through activating the PERK ER stress pathway by synergistically inducing phosphorylation/activation of PERK. Our findings add new insights into the pharmacologic effects of anti-GD2 mAb in anticancer treatment and suggest that cisplatin plus anti-GD2 mAb could be a new effective therapeutic strategy for OS.

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Document Type: Research Article

Publication date: February 1, 2018

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  • Pharmazie is a leading journal in the field of pharmaceutical sciences. As a peer-reviewed scientific journal, Pharmazie is regularly indexed in the relevant databases like Web of science, Journal Citation Reports and many others. The journal is open for submissions from the whole spectrum of pharnaceutical sciences including Pharmaceutical Chemistry, Experimental and Clinical Pharmacology, Drug Analysis, Pharmaceutics, Pharmaceutical Biology, Clinical Pharmacy etc.
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