安普克
过剩1
瓦博格效应
糖酵解
氧化磷酸化
癌细胞
癌症研究
厌氧糖酵解
葡萄糖转运蛋白
自噬
化学
生物
细胞生物学
生物化学
磷酸化
细胞凋亡
癌症
蛋白激酶A
内分泌学
新陈代谢
胰岛素
遗传学
作者
Lichao Guo,Baochen Zhang,Wen Zhang,Yanqi Xie,Xi Chen,Xiao Sun,David S. Watt,Chunming Liu,H. Peter Spielmann,Xifu Liu
出处
期刊:Cancers
[MDPI AG]
日期:2024-04-02
卷期号:16 (7): 1399-1399
标识
DOI:10.3390/cancers16071399
摘要
Cancer cells undergo a significant level of "metabolic reprogramming" or "remodeling" to ensure an adequate supply of ATP and "building blocks" for cell survival and to facilitate accelerated proliferation. Cancer cells preferentially use glycolysis for ATP production (the Warburg effect); however, cancer cells, including colorectal cancer (CRC) cells, also depend on oxidative phosphorylation (OXPHOS) for ATP production, a finding that suggests that both glycolysis and OXPHOS play significant roles in facilitating cancer progression and proliferation. Our prior studies identified a semisynthetic isoflavonoid, DBI-1, that served as an AMPK activator targeting mitochondrial complex I. Furthermore, DBI-1 and a glucose transporter 1 (GLUT1) inhibitor, BAY-876, synergistically inhibited CRC cell growth in vitro and in vivo. We now report a study of the structure-activity relationships (SARs) in the isoflavonoid family in which we identified a new DBI-1 analog, namely, DBI-2, with promising properties. Here, we aimed to explore the antitumor mechanisms of DBIs and to develop new combination strategies by targeting both glycolysis and OXPHOS. We identified DBI-2 as a novel AMPK activator using an AMPK phosphorylation assay as a readout. DBI-2 inhibited mitochondrial complex I in the Seahorse assays. We performed proliferation and Western blotting assays and conducted studies of apoptosis, necrosis, and autophagy to corroborate the synergistic effects of DBI-2 and BAY-876 on CRC cells in vitro. We hypothesized that restricting the carbohydrate uptake with a KD would mimic the effects of GLUT1 inhibitors, and we found that a ketogenic diet significantly enhanced the therapeutic efficacy of DBI-2 in CRC xenograft mouse models, an outcome that suggested a potentially new approach for combination cancer therapy.
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