低糖增强肿瘤对二甲双胍的敏感度  

Low Glucose Enhances Sensitivity of Cancer to Metformin

作　　者：张杰 丛明华 高云[3] 简美诚 徐嘉溪 缪明永[3] 石汉平 俞伟男 ZHANG Jie;CONG Minghua;GAO Yun;JIAN Meicheng;XU Jiaxi;MIAO Mingyong;SHI Hanping;YU Weinan(Department of Endocrinology, Affiliated Huai ＇an Hospital of Xuzhou Medical College, Huai ＇an 223002, China;National Cancer Center, Cancer Hospital Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China;Department of Biochemistry and Molecular Biology, College of Basic Medical Sciences, The Second Military Medical University, Shanghai 200433, China;Department of Clinical Nutrition/ General Surgery, Beijing Shijitan Hospital, Capital Medical University, Beijing 100038, China)

机构地区：[1]徐州医科大学附属淮安医院内分泌科,淮安223002 [2]国家癌症中心 中国医学科学院北京协和医学院肿瘤医院,北京100021 [3]第二军医大学基础医学部生物化学与分子生物学教研室,上海200433 [4]首都医科大学附属北京世纪坛医院普外四科/临床营养科,北京100038

出　　处：《肿瘤防治研究》2018年第3期125-130,共6页Cancer Research on Prevention and Treatment

基　　金：国家自然科学基金(81570569);国家重点研发计划项目(2017YFC1309200);山东省抗体制药协同创新中心(聊城大学)开放课题项目(CIC-AD1804)

摘　　要：目的观察不同浓度葡萄糖对二甲双胍抗肿瘤作用的影响并探讨其作用机制。方法在含不同浓度葡萄糖的培养基中加入二甲双胍培养细胞24 h后,检测细胞增殖情况及ATP水平。构建裸鼠皮下移植瘤,随机分成四组:正常饮食(SD)组、SD+二甲双胍(Met)组、生酮饮食(KD)组、KD+Met组,实验干预8周后,检测瘤体体积、重量以及裸鼠血糖水平。结果培养基中葡萄糖水平≥10 mmol/L时,二甲双胍对胰腺癌细胞增殖抑制不明显,但在低糖培养基(≤5 mmol/L)中,10mmol/L二甲双胍能明显抑制胰腺癌细胞增殖。同时,低糖培养基中各细胞ATP水平显著降低(P<0.01)。体内实验中,KD组血糖水平明显降低(P<0.01),肿瘤生长受到显著抑制(P<0.01)。与KD组相比,KD+Met组可进一步抑制移植瘤生长(P<0.05)。结论低糖增强肿瘤对二甲双胍的敏感度,其机制可能与减少机体ATP生成有关。Objective To test the effect of different glucose levels on the anti-tumor effect of metformin and explore its mechanism. Methods Cells cultured in the mediums with different glucose levels were treated with metformin for 24 hours. Then, we detected cell proliferation and ATP levels. A subcutaneous xenograft tumor model was established in nude mice in vivo. Nude mice were randomly divided into four groups： standard diet（SD） group, SD＋metformin（Met） group, ketogenic diet（KD） group and KD＋Met group. After 8 weeks of experimental intervention, tumor volume and weight and blood glucose level in nude mice were detected. Results Metformin did not inhibit the proliferation of pancreatic cancer cells when the glucose level was above 10 mmol/L, but 10 mmol/L metformin significantly inhibited the proliferation of pancreatic cancer cells in low glucose medium（≤5 mmol/L）. At the same time, the ATP level of each cell in low glucose medium was significantly decreased（P〈0.01）. In vivo, blood glucose level was significantly decreased in KD group（P〈0.01）, and KD significantly inhibited tumor growth（P〈0.01）. Compared with KD group, KD＋Met group could further inhibit the growth of the xenografts（P〈0.05）. Conclusion Low glucose enhances the sensitivity of cancer to metformin and metformin exerts anti-tumor effect by reducing the body＇s ATP production.

关 键 词：二甲双胍 生酮饮食 肿瘤 葡萄糖 

分 类 号：R459.3[医药卫生—治疗学]