metformin
Metformin use and improved response to therapy in esophageal adenocarcinoma
Atsushi Sato, Jun Sunayama, Masashi Okada, Eriko Watanabe, Shizuka Seino,
Keita Shibuya, Kaori Suzuki, Yoshitaka Narita, Soichiro Shibui, Takamasa Kayama, Chifumi Kitanaka
Stem Cells Trans Med first published on November 15, 2012; doi:10.5966/sctm.2012-0058
Cancer Stem Cells
Glioma-Initiating Cell Elimination by Metformin Activation of FOXO3 via AMPK
Control of the cancer stem/initiating cell population is considered key to realizing the long-term survival of glioblastoma patients. Recently, we demonstrated that FOXO3 activation is sufficient to induce differentiation of glioma-initiating cells having stem-like properties and inhibit their tumor-initiating potential. Here we identified metformin, an antidiabetic agent, as a therapeutic activator of FOXO3. Metformin activated FOXO3 and promoted differentiation of such stem-like glioma-initiating cells into nontumorigenic cells. Furthermore, metformin promoted FOXO3 activation and differentiation via AMP-activated protein kinase (AMPK) activation, which was sensitive to extracellular glucose availability. Importantly, transient, systemic administration of metformin depleted the self-renewing and tumor-initiating cell population within established tumors, inhibited tumor formation by stem-like glioma-initiating cells in the brain, and provided a substantial survival benefit. Our findings demonstrate that targeting glioma-initiating cells via the AMPK-FOXO3 axis is a viable therapeutic strategy against glioblastoma, with metformin being the most clinically relevant drug ever reported for targeting of glioma-initiating cells. Our results also establish a novel, direct link between glucose metabolism and cancer stem/initiating cells.
OCT1 organic cation transporter-1
Human OCT1 is mainly expressed in the liver.
LKB1
AMPK
OCT2
hOCT2 - human kidney
mTOR
Polycystic Ovarian Syndrome(PCOS)
乳腺腫瘍内科医のミシガン大学ポスドク留学日記
http://tkhawkeye.blog.fc2.com/blog-entry-284.html
メトホルミンの作用機序は、ミトコンドリア内での酸化還元反応を抑制することでAMP→ATPへの移行を抑制する。その結果AMP優位となり、
AMP-activated protein kinase（AMPK）が活性化される。その結果糖代謝の亢進やグルコースのuptakeが起こるわけだが、それと同時にmTORのカスケードを構成する因子であるRaptorやTSCを抑制することによりタンパク質の産生を抑制する。mTORはインスリンレセプターからmTOR、AKTと至るタンパク合成を促進する細胞内カスケードの中間の経路を担っているが、メトホルミンによるmTORの直接的あるいは間接的な抑制もこの経路を介した細胞増殖を抑制することにつながっている。
Biguanides suppress hepatic glucagon signalling by decreasing production of cyclic AMP
Russell A. Miller, Qingwei Chu, Jianxin Xie, Marc Foretz, Benoit Viollet & Morris J. Birnbaum
Nature 494, 256–260 (14 February 2013)
Glucose production by the liver is essential for providing a substrate for the brain during fasting. The inability of insulin to suppress hepatic glucose output is a major aetiological factor in the hyperglycaemia of type-2 diabetes mellitus and other diseases of insulin resistance1, 2. For fifty years, one of the few classes of therapeutics effective in reducing glucose production has been the biguanides, which include phenformin and metformin, the latter the most frequently prescribed drug for type-2 diabetes3. Nonetheless, the mechanism of action of biguanides remains imperfectly understood. The suggestion a decade ago that metformin reduces glucose synthesis through activation of the enzyme AMP-activated protein kinase (AMPK) has recently been challenged by genetic loss-of-function experiments4. Here we provide a novel mechanism by which metformin antagonizes the action of glucagon, thus reducing fasting glucose levels. In mouse hepatocytes, metformin leads to the accumulation of AMP and related nucleotides, which inhibit adenylate cyclase, reduce levels of cyclic AMP and protein kinase A (PKA) activity, abrogate phosphorylation of critical protein targets of PKA, and block glucagon-dependent glucose output from hepatocytes. These data support a mechanism of action for metformin involving antagonism of glucagon, and suggest an approach for the development of antidiabetic drugs.
apex @ ウィキ http://www10.atwiki.jp/apex/
最終更新：2013年12月07日 09:08
