Combined Use of Metformin and Everolimus Is Synergistic in the Treatment of Breast Cancer Cells.
Everolimus inhibits mammalian target of rapamycin (mTOR) and leads to decreased protein synthesis and decreased cancer cell proliferation in many experimental systems. Adenosine 5'-monophosphate-activated protein kinase (AMPK) activators such as metformin have similar actions in keeping with the TSC2/1 pathway linking activation of AMPK to inhibition of mTOR. Histopathological and biochemical studies of breast cancer show frequent dysregulation of the AMPK and the mTOR pathway. Therefore, we investigated the efficacy of the mTOR inhibitor everolimus and metformin in the treatment of breast cancer cells. This study evaluated the in vitro and in vivo effects of everolimus alone or in combination with metformin on breast cancer cells. MTT assay was used to quantify the inhibitory effect of the drugs on breast cancer cells in vitro. SCID mice injected with HCC1428 cells followed by different treatments were used to assess the in vivo efficacy of different agents. Data showed that the combination of everolimus and metformin exerted synergistic inhibitory effects on the growth of breast cancer cells both in culture and in a mouse xenograft model. Further, this combination abrogated S6 and 4EBP1phosphorylation. Collectively, we suggest that the combination of everolimus and metformin may be an effective regimen for treatment of breast cancer, hence warranting further evaluation of the combination in the clinic.
Department of Human Anatomy and Key Laboratory of Experimental Teratology, Ministry of Education, Shandong University School of Medicine, Jinan, Shandong, China.
Yunshan
Y
Wang
Junmin
J
Wei
Li
L
Li
Cong
C
Fan
Ying
Y
Sun
D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D018797:Cell Cycle Proteins; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D004789:Enzyme Activation; D020536:Enzyme Activators / Q000494:pharmacology*; D000068338:Everolimus / Q000494:pharmacology*; D005260:Female; D008687:Metformin / Q000494:pharmacology*; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D016513:Mice, SCID; D010750:Phosphoproteins / Q000378:metabolism; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D019893:Ribosomal Protein S6 Kinases / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D013997:Time Factors; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
D048868:Adaptor Proteins, Signal Transducing; D018797:Cell Cycle Proteins; C087000:EIF4EBP1 protein, human; D020536:Enzyme Activators; D010750:Phosphoproteins; D047428:Protein Kinase Inhibitors; D008687:Metformin; D000068338:Everolimus; C546842:MTOR protein, human; D019893:Ribosomal Protein S6 Kinases; D058570:TOR Serine-Threonine Kinases; D055372:AMP-Activated Protein Kinases