期刊
CHEMISTRY-AN ASIAN JOURNAL
卷 10, 期 3, 页码 642-652出版社
WILEY-V C H VERLAG GMBH
DOI: 10.1002/asia.201403409
关键词
apoptosis; cancer; chemoresistance; hyperglycemia; medicinal chemistry; organoselenium
资金
- National High Technology Research and Development Program of China [SS2014AA020538]
- Science Foundation for Distinguished Young Scholars of Guangdong Province
- Natural Science Foundation of China and Guangdong Province
- Research Fund for the Doctoral Program of Higher Education of China
- Foundation for High-level Talents in Higher Education of Guangdong
- YangFan Innovative & Entepreneurial Research Team Project China Post-doctoral Science Foundation [201312H05]
Hyperglycemia is an important factor for chemoresistance of hepatocellular carcinoma patients with diabetes to therapeutics. In the present study, a series of selenadiazole derivatives have been rationally designed, synthesized, and found be able to antagonize drug resistance in HepG2 cells to doxorubicin (DOX) under simulated diabetes conditions. Hyperglycemia could promote the cell proliferation through upregulation of ERK and AKT phosphorylation. However, the synthetic selenadiazole derivatives effectively potentiated the cellular uptake of DOX and enhanced the antiproliferative activity of DOX on HepG2 cells by induction of apoptosis, via regulation of ROS- mediated AMPK activation, inhibition of mTORC1, and an increase in DNA damage. The selenadiazole derivatives that possess an increased lipophilicity could enhance the cellular uptake and anticancer efficacy of DOX. Taken together, this study provides a rational design strategy of selenadiazole derivatives to overcome hyperglycemia- induced drug resistance.
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