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Selenadiazole derivatives antagonize hyperglycemia-induced drug resistance in breast cancer cells by activation of AMPK pathways

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Abstract

Hyperglycemia is an important factor for chemoresistance of breast cancer patients with diabetes. In the present study, a novel selenadiazole derivative has been evaluated and found to be able to antagonize the doxorubicin (DOX) resistance of MCF-7 cells under simulated diabetes conditions. Hyperglycemia promotes the proliferation, invasion and migration of MCF-7 cells through activation of ERK and AKT pathways, which could be inhibited by the synthetic selenadiazole derivative. The antitumor effects of the selenadiazole derivative were attributed to its ability to activate AMPK pathways. Furthermore, the high lipophilicity (log P = 1.9) of the synthetic selenadiazole derivative facilitated its uptake by cancer cells and subsequently potentiated the cellular uptake of DOX, leading to a strong enhancment of the antiproliferative activity of DOX on MCF-7 cells by induction of apoptosis. The apoptosis was initiated by the ROS overproduction induced by the cooperation of the selenadiazole derivative and DOX. The excessive ROS then caused damage to DNA, which upregulated the expression of proapoptosis Bcl-2 family proteins and led to fragmentation of mitochondria, which finally caused apoptosis of the cancer cells. Taken together, this study provides a rational strategy for using selenadiazole derivatives to overcome hyperglycemia-induced drug resistance in breast cancer by activation of AMPK-mediated pathways.

Graphical abstract: Selenadiazole derivatives antagonize hyperglycemia-induced drug resistance in breast cancer cells by activation of AMPK pathways

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Publication details

The article was received on 01 Jan 2017, accepted on 21 Mar 2017 and first published on 21 Mar 2017


Article type: Paper
DOI: 10.1039/C7MT00001D
Citation: Metallomics, 2017, Advance Article
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    Selenadiazole derivatives antagonize hyperglycemia-induced drug resistance in breast cancer cells by activation of AMPK pathways

    J. Zhao, D. Zeng, Y. Liu, Y. Luo, S. Ji, X. Li and T. Chen, Metallomics, 2017, Advance Article , DOI: 10.1039/C7MT00001D

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