PENN Medicine News - Researchers have found that a commonly prescribed diabetes drug, metformin, kills tumor cells that lack a key regulatory gene called p53.宾州新闻医学研究者们发现,一种常用的处方糖尿病药物,二甲双胍,杀死肿瘤细胞中缺少一个关键调控基因叫做p53的. Results from current studies in mice may result in new therapies for a subset of human cancers that tend to be aggressive and resistant to existing treatments.结果,从目前的小鼠研究可能导致新疗法的一个子集人类癌症往往被侵略和耐现有治疗方法. Additionally, the findings open up a new avenue for targeting cancers whose hallmark is the absence of this regulatory gene.此外,研究结果开辟了一个新途径,针对癌症,其标志是有没有这个调控基因.

The team from the University of Pennsylvania School of Medicine reported their findings last month in the journal Cancer Research .该小组由美国宾夕法尼亚大学医学院的报告,他们的研究结果于上月在癌症研究 . The study was funded by grants from the National Cancer Institute.研究拨款资助,由美国国家癌症研究所.

“This is the first time you can show that tumor growth is impaired by a diabetes drug,” says senior author Craig B. Thompson, MD, Director of the Abramson Cancer Center and Chairman and Professor of Cancer Biology and Medicine. "这是你第一次能显示肿瘤生长受到损害,糖尿病的药物,说: "资深作家克雷格汤普森乙,海事处处长余艾布拉姆逊癌症研究中心主席和教授,肿瘤生物学和医学. “It is specific for tumors that lack p53, which is the most common mutation in human cancer.” "这是特定的肿瘤缺乏p53基因,这是最常见的突变在人类癌症"

More than half of all human cancers have lost the p53 gene.超过一半的人类癌症都已经失去了p53基因. Yet even in an era of molecularly targeted therapies scientists have had trouble figuring out how to compensate for the absence of a gene.然而,即使是在当今的时代,分子靶向治疗的科学家们在盘算着如何去弥补缺少的一个基因. Unlike a genetic mutation that changes the function or activity of a gene, which can be inhibited by a well-tailored drug, loss of a gene leaves nothing for the drug to target.不同的基因突变改变了功能或活动的一个基因,它可以抑制一种非常合适的药物,失去了基因树叶什么药物目标.

Thompson and his team, however, have been accumulating evidence over the last several years that p53, best known as a regulator of cell division, controls several metabolic pathways in cells.汤普森和他的团队,但已积累证据,在过去几年中p53 ,最为人熟知的一种调节细胞分裂,控制几个代谢途径中的细胞. For potential cancer therapies, that means a drug that affects pathways controlled by p53 could help control p53-deficient tumors.潜在的癌症疗法,即药物影响到通路控制p53基因能控制p53缺失肿瘤.

Significantly, the regulation of metabolic pathways by p53 is also influenced by metformin, the most widely used diabetes drug.值得注意的是,调节代谢途径p53是影响外,还受二甲双胍,最广泛使用的糖尿病药物. Metformin activates the metabolic enzyme AMPK (AMP activated protein kinase), which exerts changes on cellular metabolism by affecting p53 function.二甲双胍活化代谢酶ampk会(安培活化蛋白激酶) ,而产生变化,对细胞代谢的影响p53功能. Two observational studies already show that diabetic patients who take metformin have a lower rate of cancer diagnosis and mortality than other diabetics.两个观测研究已经显示,糖尿病病人需二甲双胍有较低的癌症诊断和死亡率比其他糖尿病患者体内.

Thompson’s group hypothesized that metformin may specifically slow the growth of cancers that lack p53.汤姆逊集团推测二甲双胍可具体缓慢增长的癌症缺乏p53基因. To find out, they injected human colon cancer cells that have normal p53 function into one side of mice and colon cancer cells that lack p53 into the other side.为了找到答案,他们注入人体结肠癌细胞,具有正常p53功能纳入一边小鼠结肠癌细胞缺乏p53基因进入对方. Four days later they started treating the animals with a daily injection of either a saline control solution or with metformin, using a dose comparable to diabetic treatment in humans. 4天后,他们开始把动物每天注射耧生理盐水溶液或二甲双胍,使用剂量可比糖尿病治疗人类.

Four weeks later, the p53-deficient tumors in mice treated with metformin were half the size of the p53 deficient tumors in control mice.四个星期后, p53缺失小鼠的肿瘤治疗二甲双胍一半大小的p53缺失肿瘤对照组的老鼠. There was no difference in the size of the p53 normal tumors between the animals treated with metformin or saline.没有显着差异大小的p53正常与肿瘤治疗的动物二甲双胍或生理盐水. They concluded that metformin slowed the growth of the colon cancer cells that lack a normal p53 function.他们得出结论认为,二甲双胍放慢了增长的结肠癌细胞缺乏正常p53功能.

The researchers found that metformin instructs cells to switch metabolic pathways.研究者发现,二甲双胍指示细胞转换代谢途径. Instead of using the most energy efficient pathway – called oxidative phosphorylation – the cells are forced to use stress-related ones, which are typically used when the cell is short on oxygen, glucose or other nutrient sources.而是用最节省能源的通路称为氧化磷酸化细胞是被迫使用压力有关的,它通常被用来当细胞缺少氧气,葡萄糖或其它营养来源. But in the absence of p53, the cells can’t make the switch.但在缺乏p53基因,细胞不能把开关. “Without p53, if we force cells to live on alternative substrates, they can’t do it,” explains Thompson. "无p53蛋白,如果我们强迫细胞活替代物,他们不能做, "汤普森解释.

Thompson’s team is now working with collaborators to decide how best to translate these novel observations about metformin and the p53 gene in cancer into clinical practice.汤普森的团队正与合作者,以决定如何最好地把这些小说观察二甲双胍和p53基因在癌症的临床实践. If preclinical tests continue to look promising, development of metformin as a cancer therapy may move quickly as the drug is already approved by U.S. Food and Drug Administration for use in humans, the researchers surmise.如果前期测试继续看好,发展二甲双胍作为癌症治疗,可迅速为药物已经通过美国食品和药物管理局的使用在人类身上,研究者推测.