BAY 87–2243, a novel inhibitor of hypoxia-induced gene activation, improves local tumor control after fractionated irradiation in a schedule-dependent manner in head and neck human xenografts

Helbig, L.; Koi, Lydia; Brüchner, Kerstin; Gurtner, Kristin; Hess‐Stumpp, Holger; Unterschemmann, Kerstin; Baumann, Michaël; Zips, Daniel; Yaromina, Ala

doi:10.1186/1748-717x-9-207

Cited by 56 publications

(40 citation statements)

References 39 publications

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“…Consistent with previous findings [22], radiotherapy treated patients ( n = 25) with high hypoxia signature score ( n = 20) tended to have decreased overall survival ( p = 0.16) (data not shown).…”

Section: Resultssupporting

confidence: 92%

Tissue and imaging biomarkers for hypoxia predict poor outcome in endometrial cancer

et al. 2016

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Hypoxia is frequent in solid tumors and linked to aggressive phenotypes and therapy resistance. We explored expression patterns of the proposed hypoxia marker HIF-1α in endometrial cancer (EC) and investigate whether preoperative functional imaging parameters are associated with tumor hypoxia. Expression of HIF-1α was explored both in the epithelial and the stromal tumor component. We found that low epithelial HIF-1α and high stromal HIF-1α expression were significantly associated with reduced disease specific survival in EC. Only stromal HIF-1α had independent prognostic value in Cox regression analysis. High stromal HIF-1α protein expression was rare in the premalignant lesions of complex atypical hyperplasia but increased significantly to invasive cancer. High stromal HIF-1α expression was correlated with overexpression of important genes downstream from HIF-1α, i.e. VEGFA and SLC2A1 (GLUT1). Detecting hypoxic tumors with preoperative functional imaging might have therapeutic benefits. We found that high stromal HIF-1α expression associated with high total lesion glycolysis (TLG) at PET/CT. High expression of a gene signature linked to hypoxia also correlated with low tumor blood flow at DCE-MRI and increased metabolism measured by FDG-PET. PI3K pathway inhibitors were identified as potential therapeutic compounds in patients with lesions overexpressing this gene signature. In conclusion, we show that high stromal HIF-1α expression predicts reduced survival in EC and is associated with increased tumor metabolism at FDG-PET/CT. Importantly; we demonstrate a correlation between tissue and imaging biomarkers reflecting hypoxia, and also possible treatment targets for selected patients.

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Section: Resultssupporting

confidence: 92%

Tissue and imaging biomarkers for hypoxia predict poor outcome in endometrial cancer

et al. 2016

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“…This HIF-1α degradation could explain, in part, the previously reported anti-angiogenic effect of AG311 [25]. This HIF-1α destabilization by AG311 could also play a role in overcoming radioresistance [11], by re-oxygenating hypoxic tumor regions and sensitizing them to radiation therapy [49,50]. More recently, HIF-1α has been shown to induce the expression of the immune checkpoint inhibitor PD-L1 in response to hypoxia, preventing tumor attack by cytotoxic T-cells [51,52].…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2017

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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.

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“…BAY 87-2243 was previously identified from a HIF-reporter screen and was shown to block HIF-1α by targeting CI without inhibiting CIII [32]. BAY 87-2243 exhibits potent antitumor activity in vivo [32][33][34], and has recently been shown to induce mitochondrial ROS through its CI inhibitory activity [35]. As expected, we found that BAY 87-2243 blocked whole CI enzyme activity at doses as low as 5 nM in vitro but was less potent than rotenone ( Fig.…”

Section: Chchd4 Promotes Mitochondrial Ros Production In Response To mentioning

confidence: 99%

CHCHD4 confers metabolic vulnerabilities to tumour cells through its control of the mitochondrial respiratory chain

Thomas

Stephen

Esposito

et al. 2019

Preprint

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BACKGROUND: Tumour cells rely on glycolysis and mitochondrial oxidative phosphorylation (OXPHOS) to survive. Thus mitochondrial OXPHOS has become an increasingly attractive area for therapeutic exploitation in cancer. However, mitochondria are required for intracellular oxygenation and normal physiological processes, and it remains unclear which mitochondrial molecular mechanisms might provide therapeutic benefit. Previously, we discovered that coiled-coil helix coiled-coil helix domain-containing protein 4 (CHCHD4) is critical for maintaining intracellular oxygenation and required for the cellular response to hypoxia (low oxygenation) in tumour cells through molecular mechanisms that we do not yet fully understand. Overexpression of CHCHD4 in human cancers, correlates with increased tumour progression and poor patient survival.RESULTS: Here, we show that elevated CHCHD4 expression provides a proliferative and metabolic advantage to tumour cells in normoxia and hypoxia. Using stable isotope labelling with amino acids in cell culture (SILAC) and analysis of the whole mitochondrial proteome, we show that CHCHD4 dynamically affects the expression of a broad range of mitochondrial respiratory chain subunits from complex I-V, including multiple subunits of complex I (CI) required for complex assembly that are essential for cell survival. We found that loss of CHCHD4 protects tumour cells from respiratory chain inhibition at CI, while elevated CHCHD4 expression in tumour cells leads to significantly increased sensitivity to CI inhibition, in part through the production of mitochondrial reactive oxygen species (ROS). CONCLUSIONS:Our study highlights an important role for CHCHD4 in regulating tumour cell metabolism, and reveals that CHCHD4 confers metabolic vulnerabilities to tumour cells through its control of the mitochondrial respiratory chain and CI biology. BACKGROUNDMetabolic reprogramming and altered mitochondrial metabolism is a feature of cancer, and thus has become an attractive area for therapeutic exploitation [1,2]. Given the importance of mitochondria in controlling normal physiological processes, understanding how mitochondrial metabolism underlies tumorigenesis is important for ascertaining its therapeutic potential in cancer.Previously, we discovered the essential redox-sensitive mitochondrial intermembrane space (IMS) protein CHCHD4, is a critical for regulating intracellular oxygen consumption rate and metabolic responses to low oxygen (hypoxia) in tumour cells [3,4]. Overexpression of Thomas et al. 3CHCHD4 in human cancers significantly correlates with the hypoxia gene signature, tumour progression, disease recurrence and poor patient survival [3].CHCHD4 provides an import and oxidoreductase-mediated protein folding function along with the sulfhydryl oxidase GFER (ALR/Erv1) as a key part of the disulphide relay system (DRS) within the mitochondrial IMS [5][6][7]. As such, CHCHD4 controls the import of a number of mitochondrial proteins that contain a twin-CX 9 C or twin-CX 3 C motif [8][9][10].Additio...

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BAY 87–2243, a novel inhibitor of hypoxia-induced gene activation, improves local tumor control after fractionated irradiation in a schedule-dependent manner in head and neck human xenografts

Cited by 56 publications

References 39 publications

Tissue and imaging biomarkers for hypoxia predict poor outcome in endometrial cancer

Tissue and imaging biomarkers for hypoxia predict poor outcome in endometrial cancer

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

CHCHD4 confers metabolic vulnerabilities to tumour cells through its control of the mitochondrial respiratory chain

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