Targeting P-glycoprotein and SORCIN: Dihydromyricetin strengthens anti-proliferative efficiency of adriamycin via MAPK/ERK and Ca2+-mediated apoptosis pathways in MCF-7/ADR and K562/ADR

被引:47
作者
Sun, Yaoting [1 ]
Wang, Changyuan [1 ,2 ]
Meng, Qiang [1 ,2 ]
Liu, Zhihao [1 ,2 ]
Huo, Xiaokui [1 ,2 ]
Sun, Pengyuan [1 ,2 ]
Sun, Huijun [1 ,2 ]
Ma, Xiaodong [1 ,2 ]
Peng, Jinyong [1 ,2 ]
Liu, Kexin [1 ,2 ]
机构
[1] Dalian Med Univ, Dept Clin Pharmacol, Coll Pharm, 9 West Sect,Lvshun South Rd, Dalian 116044, Liaoning, Peoples R China
[2] Liaoning Dalian Med Univ, Prov Key Lab Pharmacokinet & Transport, Dalian, Liaoning, Peoples R China
基金
中国国家自然科学基金;
关键词
adriamycin; dihydromyricetin; multidrug resistance; P-glycoprotein; SORCIN; CALCIUM-BINDING PROTEIN; ENERGY-METABOLISM COMBINATION; MULTIDRUG-RESISTANCE; DRUG-RESISTANCE; 2-DEOXYGLUCOSE REVERSES; CANCER; CELLS; EXPRESSION; OVEREXPRESSION; ACTIVATION;
D O I
10.1002/jcp.26087
中图分类号
Q2 [细胞生物学];
学科分类号
071009 ; 090102 ;
摘要
Recently, a new target Ca2+-binding protein SORCIN was reported to participate in multidrug resistance (MDR) in cancer. Here we aim to investigate whether dihydromyricetin (DMY), a dihydroflavonol compound with anti-inflamatory, anti-oxidant, anti-bacterial and anti-tumor actions, reverses MDR in MCF-7/ADR and K562/ADR and to elucidate its potential molecular mechanism. DMY enhanced cytotoxicity of adriamycin (ADR) by downregulating MDR1 mRNA and P-gp expression through MAPK/ERK pathway and also inhibiting the function of P-gp significantly. Meanwhile, DMY decreased mRNA and protein expression of SORCIN, which resulted in elevating intracellular free Ca2+. Finally, we investigated co-administration ADR with DMY remarkably increased ADR-induced apoptosis. Further study showed DMY elevated ROS levels and caspase-12 protein expression, which signal apoptosis in endoplasmic reticulum. At the same time, proteins related to mitochondrial apoptosis were also changed such as Bcl-2, Bax, caspase-3, caspase-9, and PARP. Finally, nude mice model also demonstrated that DMY strengthened anti-tumor activity of ADR in vivo. In conclusion, DMY reverses MDR by downregulating P-gp, SORCIN expression and increasing free Ca2+, as well as, inducing apoptosis in MCF-7/ADR and K562/ADR. These fundamental findings provide evidence for further clinical research in application of DMY as an assistant agent in the treatment of cancer.
引用
收藏
页码:3066 / 3079
页数:14
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