AG311, a small molecule inhibitor of complex I and hypoxia-induced HIF-1α stabilization

Abstract

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.

Targeting Metabolism for Cancer Therapy

“…Consistent with this notion, other complex I inhibitors have shown efficacy as anti-tumor agents (Appleyard et al, 2012; Schockel et al, 2015) and may show selective toxicity against oncogene-ablation resistant cells (Viale et al, 2014) and cancer stem cells (Sancho et al, 2015). Additional complex I inhibitors are under development (Bastian et al, 2017), and other inhibitors of respiration or mitochondrial metabolism, including the lipoic acid derivative CPI-613 (Table 1), are currently being assessed in clinical trials (Lycan et al, 2016; Pardee et al, 2014). …”

The Mitochondrial Complex(I)ty of Cancer

“…Classic Complex I inhibitors and some new small molecules such as AG311 (74) are uncharged, aromatic and highly hydrophobic small molecules (75) that can putatively interact with the binding site of ubiquinone, producing a competitive inhibition. Generally, they have a hydroquinone/quinone motif that interacts with Complex I, and this interaction is highly sensitive to small structural changes of the inhibitors (76–78).…”

Mitochondria control acute and chronic responses to hypoxia

“…Use of these inhibitors significantly blunted the HIF-mediated response to hypoxia providing support for the hypothesis that complex III ROS are required for cellular oxygen sensing (Orr 2015). Furthermore, a recently described small molecule inhibitor of complex I which abolished the mitochondrial membrane potential also prevented hypoxic HIF stabilization (Bastian 2016). …”