Dual inhibition of tumor energy pathway by 2-deoxyglucose and metformin is effective against a broad spectrum of preclinical cancer models.
Dual inhibition of tumor energy pathway by 2-deoxyglucose and metformin is effective against a broad spectrum of preclinical cancer models.
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DOI：
10.1158/1535-7163.mct-11-0497
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发表时间：
2011-12
影响因子：
5.7
通讯作者：
Mills GB
中科院分区：
文献类型：
--
作者：
Cheong JH;Park ES;Liang J;Dennison JB;Tsavachidou D;Nguyen-Charles C;Wa Cheng K;Hall H;Zhang D;Lu Y;Ravoori M;Kundra V;Ajani J;Lee JS;Ki Hong W;Mills GB
肿瘤细胞的增殖既需要生长信号，又需要足够的细胞生物能量，AMP激活的激酶(AMPK)途径似乎主导了抑制细胞增殖的致癌信号途径。这项研究调查了糖酵解抑制剂2-脱氧葡萄糖(2DG)和AMPK激动剂AICAR和二甲双胍靶向肿瘤生物能量途径的临床前疗效。我们评价了2DG、二甲双胍或AICAR单独以及2DG与二甲双胍或AICAR合用的体外抗肿瘤活性。我们使用异种移植小鼠模型检测了体内的疗效。2DG本身不足以促进肿瘤细胞死亡，反映出临床试验显示的疗效有限。2DG和AICAR联合应用也不能诱导细胞死亡。然而，2DG和二甲双胍导致显著的细胞死亡，与细胞内ATP的减少、AMPK的延长激活和持续的自噬有关。基因表达分析和功能分析表明，选择性AMPK激动剂AICAR增强线粒体能量转导(OXPHOS)，而二甲双胍则抑制OXPHOS。重要的是，用甲基丙酮酸强制能量恢复逆转了2DG和二甲双胍诱导的细胞死亡，表明能量剥夺在细胞死亡的潜在机制中起着关键作用。2DG和二甲双胍联合应用可抑制小鼠异种移植瘤的生长。通过对能量通路的双重抑制来剥夺肿瘤的生物能量学可能是一种有效的治疗多种人类肿瘤的新方法。
Tumor cell proliferation requires both growth signals and sufficient cellular bioenergetics.The AMP-activated kinase (AMPK) pathway appears dominant over the oncogenic signaling pathway suppressing cell proliferation. This study investigated the preclinical efficacy of targeting the tumor bioenergetic pathway using a glycolysis inhibitor 2-deoxy glucose (2DG) and AMPK agonists, AICAR and metformin. We evaluated the in vitro anti-tumor activity of 2DG, metformin or AICAR alone, and 2DG in combination either with metformin or AICAR. We examined in vivo efficacy using xenograft mouse models. 2DG alone was not sufficient to promote tumor cell death, reflecting the limited efficacy demonstrated in clinical trials. A combined use of 2DG and AICAR also failed to induce cell death. However, 2DG and metformin led to significant cell death associated with decrease in cellular ATP, prolonged activation of AMPK, and sustained autophagy. Gene expression analysis and functional assays revealed that the selective AMPK agonist AICAR augments mitochondrial energy transduction (OXPHOS) while metformin compromises OXPHOS. Importantly, forced energy restoration with methylpyruvate reversed the cell death induced by 2DG and metformin, suggesting a critical role of energetic deprivation in the underlying mechanism of cell death. The combination of 2DG and metformin inhibited tumor growth in mouse xenograft models. Deprivation of tumor bioenergetics by dual inhibition of energy pathways might be an effective novel therapeutic approach for a broad spectrum of human tumors.