PDF(Pubmed)
Abstract：
Human malignancies are one of the major health-related issues throughout the world and are anticipated to rise in the future. Despite huge investments made in anticancer drug development, limited success has been obtained and the average number of FDA approvals per year is declining. So, an increasing interest in drug repurposing exists. Metformin (MET) and aspirin (ASP) possess anticancer properties. This work aims to test the effect of these two drugs in combination on colorectal cancer (CRC) cells in vitro. The effects of MET and/or ASP on cell proliferation, viability, migratory ability, anchorage-independent growth ability (colony formation), and nutrient uptake were determined in two (HT-29 and Caco-2) human CRC cell lines. Individually, MET and ASP possessed antiproliferative, cytotoxic, and antimigratory effects and reduced colony formation in HT-29 cells (BRAF- and phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit α (PI3KCA)-mutant), although MET did not affect either 3H-deoxy-D-glucose or 14C-butyrate uptake and lactate production, and ASP caused only a small decrease in 14C-butyrate uptake. Moreover, in these cells, the combination of MET and ASP resulted in a tendency to an increase in the cytotoxic effect and in a potentiation of the inhibitory effect on colony formation, although no additive antiproliferative and antimigratory effects, and no effect on nutrient uptake and lactate production were observed. In contrast, MET and ASP, both individually and in combination, were almost devoid of effects on Caco-2 cells (BRAF- and PI3KCA-wild type). We suggest that inhibition of PI3K is the common mechanism involved in the anti-CRC effect of both MET, ASP and their combination and, therefore, that the combination of MET + ASP may especially benefit PI3KCA-mutant CRC cases, which currently have a poor prognostic.
摘要：
人类恶性肿瘤是全世界与健康相关的主要问题之一,并且预期在未来会上升。尽管在抗癌药物开发方面进行了大量投资，取得了有限的成功，每年FDA批准的平均数量正在下降。所以,人们对药物再利用越来越感兴趣。二甲双胍(MET)和阿司匹林(ASP)具有抗癌特性。这项工作旨在测试这两种药物的组合对体外结直肠癌（CRC）细胞的影响。MET和/或ASP对细胞增殖的影响，生存能力，迁移能力，非锚定生长能力（集落形成），在两种（HT-29和Caco-2）人CRC细胞系中确定营养吸收。个别地,MET和ASP具有抗增殖作用，细胞毒性，以及HT-29细胞中的抗迁移作用和减少的集落形成（BRAF-和磷脂酰肌醇-4,5-二磷酸3-激酶催化亚基α（PI3KCA）-突变体），虽然MET不影响3H-脱氧-D-葡萄糖或14C-丁酸盐的摄取和乳酸的产生，ASP仅引起14C-丁酸盐吸收的少量减少。此外，在这些细胞中，MET和ASP的组合导致细胞毒性作用增加和集落形成抑制作用增强的趋势，虽然没有附加的抗增殖和抗增殖作用，对养分吸收和乳酸产生没有影响。相比之下,MET和ASP,无论是单独还是组合，对Caco-2细胞几乎没有作用(BRAF-和PI3KCA-野生型)。我们认为抑制PI3K是两种MET的抗CRC作用的共同机制。ASP及其组合，因此,MET+ASP的组合可能特别有益于PI3KCA-突变型CRC病例，目前预后较差。
