title: Selenadiazole derivatives antagonize hyperglycemia-induced drug resistance in breast cancer cells by activation of AMPK pathways.
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.
authors.affiliation: Department of Chemistry, Jinan University, Guangzhou 510632, China. tchentf@jnu.edu.cn.
authors.forename: Jianfu
authors.initials: J
authors.lastname: Zhao
authors.forename: Delong
authors.initials: D
authors.lastname: Zeng
authors.forename: Yuedan
authors.initials: Y
authors.lastname: Liu
authors.forename: Yi
authors.initials: Y
authors.lastname: Luo
authors.forename: Shengbin
authors.initials: S
authors.lastname: Ji
authors.forename: Xiaoling
authors.initials: X
authors.lastname: Li
authors.forename: Tianfeng
authors.initials: T
authors.lastname: Chen
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001940:Breast / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D049109:Cell Proliferation / Q000187:drug effects; D004317:Doxorubicin / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D020536:Enzyme Activators / Q000737:chemistry / Q000494:pharmacology*; D005260:Female; D006801:Humans; D006943:Hyperglycemia / Q000150:complications* / Q000188:drug therapy / Q000378:metabolism; D061986:MCF-7 Cells; D016566:Organoselenium Compounds / Q000737:chemistry / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects*
chemical_list: D000970:Antineoplastic Agents; D020536:Enzyme Activators; D016566:Organoselenium Compounds; D004317:Doxorubicin; D055372:AMP-Activated Protein Kinases