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Oleandrin Sensitizes Human Osteosarcoma Cells to Cisplatin by Preventing Degradation of the Copper Transporter 1

Oleandrin Sensitizes Human Osteosarcoma Cells to Cisplatin by Preventing Degradation of the Copper Transporter 1

Lei Yong, Yunlong Ma, Chen Liang, Guanping He, Zhigang Zhao, Chenlong Yang, Bao Hai, Xiaoyu Pan, Zhongjun Liu, Xiaoguang Liu

Phytother Res. 2019 Jul;33(7):1837-1850.

PMID: 31050072

Abstract:

A major problem in osteosarcoma treatment is cisplatin resistance. We have reported the anti-osteosarcoma effect of oleandrin; however, whether oleandrin sensitizes osteosarcoma to cisplatin is unknown. We investigated the chemosensitization of oleandrin and potential mechanisms in osteosarcoma cells U-2OS, SaOS-2, and MG-63. The median-effect analysis demonstrated that cisplatin + oleandrin exerted synergistic (U-2OS and MG-63) or additive effects (SaOS-2), which were consistent with the changes of the intracellular accumulation of platinum (Pt) and Pt-DNA adducts. Immunohistochemistry staining showed that the expression level of the mature form CTR1, the major influx transporter of cisplatin, was low in osteosarcoma tissue. However, oleandrin with or without cisplatin significantly increased the expression and membrane localization of the mature CTR1. Furthermore, CTR1 knockdown reversed the synergistic effect and decreased cisplatin uptake. The mRNA microarray analysis suggested that oleandrin downregulated the expression of proteasome-related genes, which was verified by the proteasome activity assay. Besides, the proteasome inhibitor MG132 upregulated the expression of the mature CTR1 in U-2OS and MG-63 cells. Overall, we conclude that oleandrin sensitizes osteosarcoma cells to cisplatin in synergistic or additive manners. The synergy results from the enhanced cisplatin uptake via oleandrin-mediated inhibition of proteasome activity and subsequent blockage of the mature CTR1 degradation.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP465167	Oleandrin		465-16-7	Price

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