Metformin synergistically sensitizes FLT3-ITD-positive acute myeloid leukemia to sorafenib by promoting mTOR-mediated apoptosis and autophagy.
Mutations of Fms-like tyrosine kinase 3-internal tandem duplication (FLT3-ITD), accounting for approximately 30% of patients with acute myeloid leukemia (AML), results in poor therapeutic efficacy and short survival. Sorafenib, an oral multikinase inhibitor, can inhibit FLT3 and improve clinical outcome of FLT3 mutated leukemia. Our current studies have shown that, the antidiabetic drug metformin also exerts anti-leukemic effect by activating p-AMPK and synergistically sensitizes FLT3 mutated AML to sorafenib. Both agents suppress cell proliferation in a dose-dependent manner and induce apoptosis via cell cycle arrest, but does not obviously modulate autophagy marker, light chain 3 (LC3). Mechanistically, in the presence of metformin, the anticancer potential of sorafenib, accompanying with increased LC3 levels, is found to be synergistically enhanced with the remarkably reduced protein expression of the mTOR/p70S6K/4EBP1 pathway, while not appreciably altering cell cycle. Overall, these results show metformin in aid of sorafenib may represent a promising and attractive strategy for the treatment of FLT3-ITD mutated AML.
Hematology Research Laboratory, Department of Hematology, West China Hospital, Sichuan University, Chengdu, Sichuan, PR China.
Fangfang
F
Wang
Hematology Research Laboratory, Department of Hematology, West China Hospital, Sichuan University, Chengdu, Sichuan, PR China; Department of Hematology, The Third People's Hospital of Chengdu, Chengdu, Sichuan, PR China.
Zuofeng
Z
Liu
Department of Tumor and Hematology, Sichuan Panzhihua Iron and Steel General Hospital, Panzhihua, Sichuan, PR China.
Jisha
J
Zeng
Laboratory of Stem Cell Biology, West China Hospital, Sichuan University, Chengdu, Sichuan, PR China.
Hongyan
H
Zhu
Laboratory Medicine, West China Hospital, Sichuan University, Chengdu, Sichuan, PR China.
Jingjing
J
Li
Hematology Research Laboratory, Department of Hematology, West China Hospital, Sichuan University, Chengdu, Sichuan, PR China.
Xiaomin
X
Cheng
Department of Hematology, Sichuan Provincial People's Hospital, Chengdu, Sichuan, PR China.
Tao
T
Jiang
Hematology Research Laboratory, Department of Hematology, West China Hospital, Sichuan University, Chengdu, Sichuan, PR China.
Li
L
Zhang
Hematology Research Laboratory, Department of Hematology, West China Hospital, Sichuan University, Chengdu, Sichuan, PR China.
Chuanfen
C
Zhang
Health Science Center, Shenzhen University, Shenzhen, PR China.
Tie
T
Chen
Hematology Research Laboratory, Department of Hematology, West China Hospital, Sichuan University, Chengdu, Sichuan, PR China.
Ting
T
Liu
Hematology Research Laboratory, Department of Hematology, West China Hospital, Sichuan University, Chengdu, Sichuan, PR China. Electronic address: jia_yq@163.com.
Yongqian
Y
Jia
D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001343:Autophagy / Q000187:drug effects; D015415:Biomarkers; D002453:Cell Cycle / Q000187:drug effects; D018797:Cell Cycle Proteins; D045744:Cell Line, Tumor; D004357:Drug Synergism; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000473:pathology*; D008687:Metformin / Q000494:pharmacology*; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D058990:Molecular Targeted Therapy; D009154:Mutation; D009363:Neoplasm Proteins / Q000502:physiology; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000378:metabolism; D009536:Niacinamide / Q000031:analogs & derivatives* / Q000494:pharmacology; D010671:Phenylurea Compounds / Q000494:pharmacology*; D010750:Phosphoproteins / Q000378:metabolism; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011499:Protein Processing, Post-Translational; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D000077157:Sorafenib; D058570:TOR Serine-Threonine Kinases / Q000502:physiology*; D020080:Tandem Repeat Sequences; D051941:fms-Like Tyrosine Kinase 3 / Q000235:genetics*
D048868:Adaptor Proteins, Signal Transducing; D000970:Antineoplastic Agents; D015415:Biomarkers; D018797:Cell Cycle Proteins; C087000:EIF4EBP1 protein, human; C477012:MAP1LC3A protein, human; D008869:Microtubule-Associated Proteins; D009363:Neoplasm Proteins; D010671:Phenylurea Compounds; D010750:Phosphoproteins; D047428:Protein Kinase Inhibitors; D009536:Niacinamide; D008687:Metformin; D000077157:Sorafenib; C546842:MTOR protein, human; C497970:FLT3 protein, human; D051941:fms-Like Tyrosine Kinase 3; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D058570:TOR Serine-Threonine Kinases; D055372:AMP-Activated Protein Kinases
Acute myeloid leukemia; Apoptosis; FLT-ITD; Metformin; Sorafenib