title: Metformin displays anti-myeloma activity and synergistic effect with dexamethasone in in vitro and in vivo xenograft models.
abstract: Epidemiologic studies and meta-analyses have suggested that patients with type 2 diabetes mellitus (T2DM) have a higher incidence of malignancies, including myeloma. Metformin is a widely prescribed antidiabetic drug. Recently, researchers have shown that metformin has direct anticancer activity against many tumor cell lines, mainly through activating AMP-activated protein kinase (AMPK) or reducing the blood insulin level. In the present study, we investigated whether metformin exerts an anti-myeloma effect in in vitro and in vivo xenograft models and explored the underlying mechanism. We found that metformin can inhibit proliferation of MM cells by inducing apoptosis and cell cycle arrest in the G0/G1 phase. Western blot showed that metformin activated caspase 3, caspase 9, PARP-1, Bak, and p21 and inactivated Mcl-1, HIAP-1, cyclin D1, CDK4, and CDK6. Metformin inhibited the expression of insulin growth factor-I receptor (IGF-IR), and phosphatidyl inositol 3-kinase (PI3K), protein kinase B (PKB/AKT) and the downstream mammalian target of rapamycin (mTOR). IGF-I blocked metformin-induced MM cell apoptosis and reactivation of the PI3K/AKT/mTOR signaling pathway. Metformin also demonstrated synergistic activity with dexamethasone but not bortezomib to eradicate MM cells in vitro and in vivo, especially in MM.1S cells. We conclude that metformin inhibits MM cell proliferation through the IGF-1R/PI3K/AKT/mTOR signaling pathway. Metformin and dexamethasone combination therapy may be an option for MM treatment.
authors.affiliation: Bone Marrow Transplantation Center, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.
authors.forename: Fu-Ming
authors.initials: FM
authors.lastname: Zi
authors.affiliation: Bone Marrow Transplantation Center, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.
authors.forename: Jing-Song
authors.initials: JS
authors.lastname: He
authors.affiliation: Bone Marrow Transplantation Center, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Li
authors.affiliation: Bone Marrow Transplantation Center, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.
authors.forename: Cai
authors.initials: C
authors.lastname: Wu
authors.affiliation: Bone Marrow Transplantation Center, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.
authors.forename: Li
authors.initials: L
authors.lastname: Yang
authors.affiliation: Bone Marrow Transplantation Center, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Yang
authors.affiliation: Bone Marrow Transplantation Center, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.
authors.forename: Li-Juan
authors.initials: LJ
authors.lastname: Wang
authors.affiliation: Bone Marrow Transplantation Center, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.
authors.forename: Dong-Hua
authors.initials: DH
authors.lastname: He
authors.affiliation: Bone Marrow Transplantation Center, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Zhao
authors.affiliation: Bone Marrow Transplantation Center, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.
authors.forename: Wen-Jun
authors.initials: WJ
authors.lastname: Wu
authors.affiliation: Bone Marrow Transplantation Center, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.
authors.forename: Gao-Feng
authors.initials: GF
authors.lastname: Zheng
authors.affiliation: Bone Marrow Transplantation Center, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.
authors.forename: Xiao-Yan
authors.initials: XY
authors.lastname: Han
authors.affiliation: Bone Marrow Transplantation Center, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.
authors.forename: He
authors.initials: H
authors.lastname: Huang
authors.affiliation: Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA.
authors.forename: Qing
authors.initials: Q
authors.lastname: Yi
authors.affiliation: Bone Marrow Transplantation Center, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China. Electronic address: caiz@zju.edu.cn.
authors.forename: Zhen
authors.initials: Z
authors.lastname: Cai
mesh_terms: D000818:Animals; D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D002453:Cell Cycle / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D003907:Dexamethasone / Q000494:pharmacology*; D004357:Drug Synergism; D005434:Flow Cytometry; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D007124:Immunoenzyme Techniques; D008297:Male; D008687:Metformin / Q000494:pharmacology*; D051379:Mice; D016513:Mice, SCID; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000473:pathology; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: D018931:Antineoplastic Agents, Hormonal; D007004:Hypoglycemic Agents; D012333:RNA, Messenger; D003907:Dexamethasone; D008687:Metformin
keywords: Apoptosis; Cell cycle arrest; Mechanism; Metformin; Multiple myeloma