來(lái)自Pennsylvania大學(xué)醫(yī)學(xué)院的科學(xué)家最近發(fā)現(xiàn)，一種常見的治療糖尿病的藥物能殺死缺少關(guān)鍵調(diào)控基因p53的癌細(xì)胞,。這一結(jié)果可能為人類難以治愈的癌癥帶來(lái)新的治療手段,。結(jié)果發(fā)表在Cancer Research上,。
超過(guò)一半的人類癌癥失去了p53基因,。不像由基因變異導(dǎo)致的單個(gè)基因的功能或活性的變化,，它們能通過(guò)藥物得到控制，而基因的缺失無(wú)法通過(guò)藥物進(jìn)行治療,。主要作者Craig B. Thompson和他的小組在過(guò)去數(shù)年間證實(shí),，p53——這一細(xì)胞分裂的調(diào)控者，同時(shí)控制著多個(gè)細(xì)胞代謝途徑,。這意味著找到影響p53控制的代謝途徑的藥物,，就可以控制p53缺失導(dǎo)致的癌癥。
p53控制的代謝途徑同時(shí)能被甲福明二甲雙胍影響,，這是一種廣泛用于糖尿病治療的藥物,。它激活代謝酶AMPK，然后通過(guò)影響p53的功能而改變細(xì)胞代謝,。
Thompson小組認(rèn)為該藥物能降低缺少p53的癌細(xì)胞生長(zhǎng),。他們將p53正常的人類腸癌細(xì)胞和缺少p53的癌細(xì)胞分別注入老鼠兩側(cè)。4天后科學(xué)家分別為老鼠注射鹽水溶液或藥物,，劑量和人類糖尿病治療中的相當(dāng),。4周后，用藥物處理的缺少p53的腫瘤是對(duì)照組的一半,，而p53正常的腫瘤細(xì)胞沒有差異,。因此科學(xué)家認(rèn)為該藥物可以降低缺少p53的腸癌細(xì)胞生長(zhǎng)。
小組發(fā)現(xiàn)藥物使細(xì)胞開關(guān)代謝途徑,。而在缺少p53的細(xì)胞中,，它們無(wú)法實(shí)現(xiàn)這樣的開關(guān)。Thompson小組目前正在和其它機(jī)構(gòu)合作,，希望能將這些新發(fā)現(xiàn)最有效的轉(zhuǎn)化為臨床上的應(yīng)用,。（教育部科技發(fā)展中心）
原文鏈接：http://www.physorg.com/news106324980.html
原始出處:
Cancer Research 67, 6745-6752, July 15, 2007. doi: 10.1158/0008-5472.CAN-06-4447
Cell, Tumor, and Stem Cell Biology
Systemic Treatment with the Antidiabetic Drug Metformin Selectively Impairs p53-Deficient Tumor Cell Growth
Monica Buzzai1, Russell G. Jones1, Ravi K. Amaravadi1,2, Julian J. Lum1, Ralph J. DeBerardinis1,3, Fangping Zhao1, Benoit Viollet4,5 and Craig B. Thompson1
1 Abramson Family Cancer Research Institute, Department of Cancer Biology; 2 Division of Hematology-Oncology, Department of Medicine, University of Pennsylvania; 3 Division of Child Development, Rehabilitation Medicine and Metabolic Disease, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania; 4 Institut Cochin, Université Paris Descartes, Centre National de la Recherche Scientifique (UMR 8104); and 5 Inserm, U567, Paris, France
Requests for reprints: Craig B. Thompson, Abramson Family Cancer Research Institute, Department of Cancer Biology, University of Pennsylvania, Philadelphia, PA 19104. Phone: 215-746-5515; Fax: 215-746-5511; E-mail: [email protected] .
The effect of the antidiabetic drug metformin on tumor growth was investigated using the paired isogenic colon cancer cell lines HCT116 p53+/+ and HCT116 p53–/–. Treatment with metformin selectively suppressed the tumor growth of HCT116 p53–/– xenografts. Following treatment with metformin, we detected increased apoptosis in p53–/– tumor sections and an enhanced susceptibility of p53–/– cells to undergo apoptosis in vitro when subject to nutrient deprivation. Metformin is proposed to function in diabetes treatment as an indirect activator of AMP-activated protein kinase (AMPK). Treatment with AICAR, another AMPK activator, also showed a selective ability to inhibit p53–/– tumor growth in vivo. In the presence of either of the two drugs, HCT116 p53+/+ cells, but not HCT116 p53–/– cells, activated autophagy. A similar p53-dependent induction of autophagy was observed when nontransformed mouse embryo fibroblasts were treated. Treatment with either metformin or AICAR also led to enhanced fatty acid ß-oxidation in p53+/+ MEFs, but not in p53–/– MEFs. However, the magnitude of induction was significantly lower in metformin-treated cells, as metformin treatment also suppressed mitochondrial electron transport. Metformin-treated cells compensated for this suppression of oxidative phosphorylation by increasing their rate of glycolysis in a p53-dependent manner. Together, these data suggest that metformin treatment forces a metabolic conversion that p53–/– cells are unable to execute. Thus, metformin is selectively toxic to p53-deficient cells and provides a potential mechanism for the reduced incidence of tumors observed in patients being treated with metformin. [Cancer Res 2007;67(14):6745–52]
