Trametinib modulates cancer multidrug resistance by targeting ABCB1 transporter.
Overexpression of adenine triphosphate (ATP)-binding cassette (ABC) transporters is one of the main reasons of multidrug resistance (MDR) in cancer cells. Trametinib, a novel specific small-molecule mitogen-activated extracellular signal-regulated kinase (MEK) inhibitor, is currently used for the treatment of melanoma in clinic. In this study, we investigated the effect of trametinib on MDR mediated by ABC transporters. Trametinib significantly potentiated the effects of two ABCB1 substrates vincristine and doxorubicin on inhibition of growth, arrest of cell cycle and induction of apoptosis in cancer cells overexpressed ABCB1, but not ABCC1 and ABCG2. Furthermore, trametinib did not alter the sensitivity of non-ABCB1 substrate cisplatin. Mechanistically, trametinib potently blocked the drug-efflux activity of ABCB1 to increase the intracellular accumulation of rhodamine 123 and doxorubicin and stimulates the ATPase of ABCB1 without alteration of the expression of ABCB1. Importantly, trametinib remarkably enhanced the effect of vincristine against the xenografts of ABCB1-overexpressing cancer cells in nude mice. The predicted binding mode showed the hydrophobic interactions of trametinib within the large drug binding cavity of ABCB1. Consequently, our findings may have important implications for use of trametinib in combination therapy for cancer treatment.
Department of Cell Biology and Institute of Biomedicine, College of Life Science and Technology, Jinan University, National Engineering Research Center of Genetic Medicine, Guangdong Provincial Key Laboratory of Bioengineering Medicine, Guangzhou, Guangdong, China.
Jian-Ge
JG
Qiu
Department of Hepatobiliary Surgery, Cancer Center, Sun Yat-Sen University, Guangzhou, Guangdong, China.
Yao-Jun
YJ
Zhang
Department of Gastrointertinal Surgery and General Surgery, Guangdong General Hospital, Guangdong Academy of Medical Sciences, Guangzhou, Guangdong, China.
Yong
Y
Li
Department of Thoracic Surgery, The Sixth Affiliated Hospital, Sun Yat-Sen University, Guangzhou, Guangdong, China.
Jin-Ming
JM
Zhao
Department of Cell Biology and Institute of Biomedicine, College of Life Science and Technology, Jinan University, National Engineering Research Center of Genetic Medicine, Guangdong Provincial Key Laboratory of Bioengineering Medicine, Guangzhou, Guangdong, China.
Wen-Ji
WJ
Zhang
Department of Cell Biology and Institute of Biomedicine, College of Life Science and Technology, Jinan University, National Engineering Research Center of Genetic Medicine, Guangdong Provincial Key Laboratory of Bioengineering Medicine, Guangzhou, Guangdong, China.
Qi-Wei
QW
Jiang
Department of Cell Biology and Institute of Biomedicine, College of Life Science and Technology, Jinan University, National Engineering Research Center of Genetic Medicine, Guangdong Provincial Key Laboratory of Bioengineering Medicine, Guangzhou, Guangdong, China.
Xiao-Long
XL
Mei
Department of Cell Biology and Institute of Biomedicine, College of Life Science and Technology, Jinan University, National Engineering Research Center of Genetic Medicine, Guangdong Provincial Key Laboratory of Bioengineering Medicine, Guangzhou, Guangdong, China.
You-Qiu
YQ
Xue
Department of Cell Biology and Institute of Biomedicine, College of Life Science and Technology, Jinan University, National Engineering Research Center of Genetic Medicine, Guangdong Provincial Key Laboratory of Bioengineering Medicine, Guangzhou, Guangdong, China.
Wu-Ming
WM
Qin
Department of Cell Biology and Institute of Biomedicine, College of Life Science and Technology, Jinan University, National Engineering Research Center of Genetic Medicine, Guangdong Provincial Key Laboratory of Bioengineering Medicine, Guangzhou, Guangdong, China.
Yang
Y
Yang
Department of Cell Biology and Institute of Biomedicine, College of Life Science and Technology, Jinan University, National Engineering Research Center of Genetic Medicine, Guangdong Provincial Key Laboratory of Bioengineering Medicine, Guangzhou, Guangdong, China.
Di-Wei
DW
Zheng
Department of Cell Biology and Institute of Biomedicine, College of Life Science and Technology, Jinan University, National Engineering Research Center of Genetic Medicine, Guangdong Provincial Key Laboratory of Bioengineering Medicine, Guangzhou, Guangdong, China.
Yao
Y
Chen
Department of Cell Biology and Institute of Biomedicine, College of Life Science and Technology, Jinan University, National Engineering Research Center of Genetic Medicine, Guangdong Provincial Key Laboratory of Bioengineering Medicine, Guangzhou, Guangdong, China.
Meng-Ning
MN
Wei
Department of Cell Biology and Institute of Biomedicine, College of Life Science and Technology, Jinan University, National Engineering Research Center of Genetic Medicine, Guangdong Provincial Key Laboratory of Bioengineering Medicine, Guangzhou, Guangdong, China.
Zhi
Z
Shi
D018435:ATP Binding Cassette Transporter, Subfamily B / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000187:drug effects; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000473:pathology; D059447:Cell Cycle Checkpoints / Q000187:drug effects*; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000494:pharmacology; D004317:Doxorubicin / Q000494:pharmacology; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D061986:MCF-7 Cells; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D062105:Molecular Docking Simulation; D009036:Moths; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000187:drug effects; D009363:Neoplasm Proteins / Q000187:drug effects; D011728:Pyridones / Q000494:pharmacology*; D011744:Pyrimidinones / Q000494:pharmacology*; D020112:Rhodamine 123 / Q000494:pharmacology; D014750:Vincristine / Q000494:pharmacology; D023041:Xenograft Model Antitumor Assays
D018435:ATP Binding Cassette Transporter, Subfamily B; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D002945:Cisplatin; D004317:Doxorubicin; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D009363:Neoplasm Proteins; D011728:Pyridones; D011744:Pyrimidinones; D020112:Rhodamine 123; D014750:Vincristine; C513055:ABCB1 protein, human; C116614:ABCG2 protein, human; C560077:trametinib; C421109:multidrug resistance-associated protein 1
ABCB1; chemotherapy; multidrug resistance; trametinib