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Targeting P‐glycoprotein and SORCIN: Dihydromyricetin strengthens anti‐proliferative efficiency of adriamycin via MAPK/ERK and Ca 2+ ‐mediated apoptosis pathways in MCF‐7/ADR and K562/ADR
Author(s) -
Sun Yaoting,
Wang Changyuan,
Meng Qiang,
Liu Zhihao,
Huo Xiaokui,
Sun Pengyuan,
Sun Huijun,
Ma Xiaodong,
Peng Jinyong,
Liu Kexin
Publication year - 2018
Publication title -
journal of cellular physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.529
H-Index - 174
eISSN - 1097-4652
pISSN - 0021-9541
DOI - 10.1002/jcp.26087
Subject(s) - apoptosis , mapk/erk pathway , k562 cells , p glycoprotein , endoplasmic reticulum , caspase 3 , chemistry , pharmacology , caspase , microbiology and biotechnology , biology , cancer research , signal transduction , multiple drug resistance , biochemistry , programmed cell death , antibiotics
Recently, a new target Ca 2+ ‐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 Ca 2+ . 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 Ca 2+ , 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.