AG311, a small molecule inhibitor of complex I and hypoxia-induced HIF-1α stabilization.
AG311, a small molecule inhibitor of complex I and hypoxia-induced HIF-1α stabilization.
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DOI：
10.1016/j.canlet.2016.11.040
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发表时间：
2017-03-01
期刊：
影响因子：
9.7
通讯作者：
Ihnat MA
中科院分区：
文献类型：
--
作者：
Bastian A;Matsuzaki S;Humphries KM;Pharaoh GA;Doshi A;Zaware N;Gangjee A;Ihnat MA
癌细胞具有独特的代谢特征，并且线粒体已被证明在化学抗性、肿瘤进展和转移中起重要作用。这种独特的特征可以被神经靶向抗癌疗法所利用。一个小的抗癌分子，AG 311，先前被证明具有抗癌和抗转移活性，在两个癌症小鼠模型，并诱导线粒体去极化。本研究定义了AG 311对线粒体的分子效应，以阐明其观察到的疗效。发现AG 311竞争性抑制复合物I在泛醌结合位点的活性。通过测量从经AG 311处理的小鼠分离的肿瘤组织中的耗氧速率，进一步确立了作为AG 311的靶标的复合物I。用AG 311和二氯乙酸（一种增加氧化代谢的丙酮酸脱氢酶激酶抑制剂）共处理细胞和动物，导致协同细胞杀伤和减少肿瘤生长。发现AG 311抑制线粒体氧消耗通过增加缺氧条件下的氧张力来降低HIF-1α的稳定性。综上所述，这些结果表明，AG 311至少部分介导其抗肿瘤作用，通过抑制复合物I，这可以利用其作为抗癌剂的用途。
Cancer cells have a unique metabolic profile and mitochondria have been shown to play an important role in chemoresistance, tumor progression and metastases. This unique profile can be exploited by mitochondrial-targeted anticancer therapies. A small anticancer molecule, AG311, was previously shown to possess anticancer and antimetastatic activity in two cancer mouse models and to induce mitochondrial depolarization. This study defines the molecular effects of AG311 on the mitochondria to elucidate its observed efficacy. AG311 was found to competitively inhibit complex I activity at the ubiquinone-binding site. Complex I as a target for AG311 was further established by measuring oxygen consumption rate in tumor tissue isolated from AG311-treated mice. Cotreatment of cells and animals with AG311 and dichloroacetate, a pyruvate dehydrogenase kinase inhibitor that increases oxidative metabolism, resulted in synergistic cell kill and reduced tumor growth. The inhibition of mitochondrial oxygen consumption by AG311 was found to reduce HIF-1α stabilization by increasing oxygen tension in hypoxic conditions. Taken together, these results suggest that AG311 at least partially mediates its antitumor effect through inhibition of complex I, which could be exploited in its use as an anticancer agent.