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Rational Design of Selenadiazole Derivatives to Antagonize Hyperglycemia‐Induced Drug Resistance in Cancer Cells
Author(s) -
Liu Yuedan,
Luo Yi,
Li Xiaoling,
Zheng Wenjie,
Chen Tianfeng
Publication year - 2015
Publication title -
chemistry – an asian journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.18
H-Index - 106
eISSN - 1861-471X
pISSN - 1861-4728
DOI - 10.1002/asia.201403409
Subject(s) - mtorc1 , pharmacology , ampk , mapk/erk pathway , downregulation and upregulation , apoptosis , chemistry , protein kinase b , cancer cell , cancer , medicine , signal transduction , biochemistry , kinase , protein kinase a , gene
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.