PDF(Pubmed)
Abstract：
The effect of agonists on AMP-activated protein kinase (AMPK), mainly metformin and phenformin, has been appreciated in the treatment of multiple types of tumors. Specifically, the antitumor activity of phenformin has been demonstrated in melanomas containing the v-Raf murine sarcoma viral oncogene homolog B1 (BRAF) activating mutation. In this report, we elucidated the synergistic antitumor effects of biguanides with metabolism inhibitors on colon tumors. Phenformin with 2-deoxy-D-glucose (2DG) inhibited tumor cell growth in cancer cell lines, including HT29 cells harboring BRAF- and p53-mutations. Biochemical analyses showed that two chemotherapeutics exerted cooperative effects to reduce tumor growth through cell cycle arrest, apoptosis, and autophagy. The drugs demonstrated activity against phosphorylated ERK and the gain-of-function p53 mutant protein. To demonstrate tumor regressive effects in vivo, we established patient-derived models, including xenograft (PDX) and organoids (PDO). Co-treatment of biguanides with chemotherapeutics efficiently reduced the growth of patient-derived colon models in comparison to treatment with a single agent. These results strongly suggest that significant therapeutic advantages would be achieved by combining AMPK activators such as phenformin and cancer metabolic inhibitors such as 2DG.
摘要：
激动剂对AMP激活的蛋白激酶（AMPK）的影响，主要是二甲双胍和苯乙双胍,在多种肿瘤的治疗中受到了重视。具体来说,苯乙双胍的抗肿瘤活性已在含有v-Raf鼠肉瘤病毒癌基因同源物B1(BRAF)激活突变的黑色素瘤中得到证实.在这份报告中,我们阐明了双胍与代谢抑制剂对结肠肿瘤的协同抗肿瘤作用。苯乙双胍与2-脱氧-D-葡萄糖（2DG）抑制癌细胞系的肿瘤细胞生长，包括携带BRAF和p53突变的HT29细胞。生化分析表明，两种化学疗法发挥协同作用，通过细胞周期阻滞减少肿瘤生长，凋亡，和自噬。这些药物显示了对磷酸化ERK和功能获得p53突变蛋白的活性。为了证明体内的肿瘤消退效应，我们建立了患者衍生模型，包括异种移植物(PDX)和类器官(PDO)。与用单一药剂治疗相比,双胍与化疗剂的共治疗有效地减少了患者衍生的结肠模型的生长。这些结果强烈地表明,通过组合AMPK激活剂如苯乙双胍和癌症代谢抑制剂如2DG将获得显著的治疗优势。
