来自Pennsylvania大学医学院的科学家最近发现，一种常见的治疗糖尿病的药物能杀死缺少关键调控基因p53的癌细胞。这一结果可能为人类难以治愈的癌症带来新的治疗手段。结果发表在Cancer Research上。
超过一半的人类癌症失去了p53基因。不像由基因变异导致的单个基因的功能或活性的变化，它们能通过药物得到控制，而基因的缺失无法通过药物进行治疗。主要作者Craig B. Thompson和他的小组在过去数年间证实，p53——这一细胞分裂的调控者，同时控制着多个细胞代谢途径。这意味着找到影响p53控制的代谢途径的药物，就可以控制p53缺失导致的癌症。
p53控制的代谢途径同时能被甲福明二甲双胍影响，这是一种广泛用于糖尿病治疗的药物。它激活代谢酶AMPK，然后通过影响p53的功能而改变细胞代谢。
Thompson小组认为该药物能降低缺少p53的癌细胞生长。他们将p53正常的人类肠癌细胞和缺少p53的癌细胞分别注入老鼠两侧。4天后科学家分别为老鼠注射盐水溶液或药物，剂量和人类糖尿病治疗中的相当。4周后，用药物处理的缺少p53的肿瘤是对照组的一半，而p53正常的肿瘤细胞没有差异。因此科学家认为该药物可以降低缺少p53的肠癌细胞生长。
小组发现药物使细胞开关代谢途径。而在缺少p53的细胞中，它们无法实现这样的开关。Thompson小组目前正在和其它机构合作，希望能将这些新发现最有效的转化为临床上的应用。（教育部科技发展中心）
原文链接：http://www.physorg.com/news106324980.html
原始出处:
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: craig@mail.med.upenn.edu .
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]
