El-Ashmawy Nahla E, Khedr Naglaa F, El-Bahrawy Hoda A, Abo Mansour Hend E
Department of Biochemistry, Faculty of Pharmacy, Tanta University, Tanta, Egypt.
Tumour Biol. 2017 May;39(5):1010428317692235. doi: 10.1177/1010428317692235.
Since the incidence of breast cancer increases dramatically all over the world, the search for effective treatment is an urgent need. Metformin has demonstrated anti-tumorigenic effect both in vivo and in vitro in different cancer types. This work was designed to examine on molecular level the mode of action of metformin in mice bearing solid Ehrlich carcinoma and to evaluate the use of metformin in conjunction with doxorubicin as a combined therapy against solid Ehrlich carcinoma. Ehrlich ascites carcinoma cells were inoculated in 60 female mice as a model of breast cancer. The mice were divided into four equal groups: Control tumor, metformin, doxorubicin, and co-treatment. Metformin (15 mg/kg) and doxorubicin (4 mg/kg) were given intraperitoneally (i.p.) for four cycles every 5 days starting on day 12 of inoculation. The anti-tumorigenic effect of metformin was mediated by enhancement of adenosine monophosphate protein kinase activity and elevation of P53 protein as well as the suppression of nuclear factor-kappa B, DNA contents, and cyclin D1 gene expression. Metformin and doxorubicin mono-treatments exhibited opposing action regarding cyclin D1 gene expression, phosphorylated adenosine monophosphate protein kinase, and nuclear factor-kappa B levels. Co-treatment markedly decreased tumor volume, increased survival rate, and improved other parameters compared to doxorubicin group. In parallel, the histopathological findings demonstrated enhanced apoptosis and absence of necrosis in tumor tissue of co-treatment group. Metformin proved chemotherapeutic effect which could be mediated by the activation of adenosine monophosphate protein kinase and related pathways. Combining metformin and doxorubicin, which exhibited different mechanisms of action, produced greater efficacy as anticancer therapeutic regimen.
由于全球乳腺癌发病率急剧上升，寻求有效的治疗方法成为当务之急。二甲双胍在不同癌症类型的体内和体外实验中均显示出抗肿瘤作用。本研究旨在从分子水平研究二甲双胍对荷实体艾氏癌小鼠的作用模式，并评估二甲双胍与阿霉素联合治疗实体艾氏癌的效果。将艾氏腹水癌细胞接种于60只雌性小鼠，作为乳腺癌模型。小鼠被分为四组，每组数量相等：对照肿瘤组、二甲双胍组、阿霉素组和联合治疗组。从接种后第12天开始，每5天腹腔注射一次二甲双胍（15mg/kg）和阿霉素（4mg/kg），共四个周期。二甲双胍的抗肿瘤作用是通过增强单磷酸腺苷蛋白激酶活性、提高P53蛋白水平以及抑制核因子κB、DNA含量和细胞周期蛋白D1基因表达来介导的。二甲双胍和阿霉素单药治疗在细胞周期蛋白D1基因表达、磷酸化单磷酸腺苷蛋白激酶和核因子κB水平方面表现出相反的作用。与阿霉素组相比，联合治疗显著降低了肿瘤体积，提高了生存率，并改善了其他参数。同时，组织病理学结果显示联合治疗组肿瘤组织的凋亡增强且无坏死。二甲双胍具有化疗作用，可通过激活单磷酸腺苷蛋白激酶及相关途径来介导。二甲双胍和阿霉素作用机制不同，联合使用作为抗癌治疗方案具有更高的疗效。
