Article
The prolyl hydroxylase-inhibitor EDHB enhances postsurgical liver function without affecting metastatic tumor growth
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Authors
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Jonathan Michael Harnoss
- Universitätsklinikum Heidelberg, Chirurgische Klinik, Abteilung für Allgemein-, Viszeral- und Transplantationschirurgie, Heidelberg, Deutschland
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Lisa Platzer
- Universitätsklinikum Heidelberg, Chirurgische Klinik, Abteilung für Allgemein-, Viszeral- und Transplantationschirurgie, Heidelberg, Deutschland
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Praveen Radhakrishnan
- Universitätsklinikum Heidelberg, Chirurgische Klinik, Abteilung für Allgemein-, Viszeral- und Transplantationschirurgie, Heidelberg, Deutschland
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Jun Cai
- Universitätsklinikum Heidelberg, Chirurgische Klinik, Abteilung für Allgemein-, Viszeral- und Transplantationschirurgie, Heidelberg, Deutschland
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Jürgen Burhenne
- Universitätsklinikum Heidelberg, Medizinische Klinik, Abteilung für Klinische Pharmakologie und Pharmakoepidemiologie, Heidelberg, Deutschland
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Walter E. Haefeli
- Universitätsklinikum Heidelberg, Medizinische Klinik, Abteilung für Klinische Pharmakologie und Pharmakoepidemiologie, Heidelberg, Deutschland
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Alexis Ulrich
- Universitätsklinikum Heidelberg, Chirurgische Klinik, Abteilung für Allgemein-, Viszeral- und Transplantationschirurgie, Heidelberg, Deutschland
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Martin Schneider
- Universitätsklinikum Heidelberg, Chirurgische Klinik, Abteilung für Allgemein-, Viszeral- und Transplantationschirurgie, Heidelberg, Deutschland
| Published: | April 24, 2015 |
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Outline
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Introduction: Hypoxia and increased stabilization of hypoxia inducible factors (HIF-1 and -2) are common in a variety of tumors, and associated with increased tumor invasiveness and metastasis. On the other hand, HIF prolyl-hydroxylase (PHD) enzymes are putative pharmacological targets for enhancing liver function following major liver resections. However, the specific impact of pharmacological PHD-inhibitors on tumor growth remains elusive. Here, we aimed to assess the effects of the PHD-inhibitor ethyl-dihydroxybenzoate (EDHB) on colorectal liver metastases.
Material and methods: Mice were pre-treated with EDHB (100mg/kg) for 5 days, and subsequently subjected to warm liver ischemia/reperfusion (I/R), 80%-hepatectomy (PHx) or 75% portal vein ligation (PVL). Syngenic mouse models of orthotopic- and metastatic colorectal cancer growth were applied to test the effects of EDHB or the HIF-inhibitor YC-1 (30 mg/kg for 12 days) on tumor spread. To mimic surgical treatment approaches, mice carrying colorectal liver metastases underwent PHx or PVL plus simultaneous treatment with EDHB. Blood and urine was sampled for assessment of EDHB-metabolites, and hepatic or subcutaneous tumors were harvested for molecular analyses and histology.
Results: After 5 days of treatment, EDHB metabolites could be detected in the plasma, in liver lysates (DHB) and in the urine (EDHB-glucoronide). Pharmacologic inhibition of PHD enzymes significantly reduced liver I/R injury, but did not stimulate liver regeneration in the tested models of PHx or PVL. Importantly, however, EDHB-treatment affected the expansion of colorectal liver metastases neither in orthotopic, nor in heterotopic models, while YC-1 treatment expectedly reduced tumor growth.
Conclusion: The PHD-inhibitor EDHB enhances postsurgical liver function, but does not stimulate metastatic tumor growth in a pre-clinical mouse model. EDHB may therefore represent a suitable small-molecule drug for the pharmacological inhibition of PHD-enzymes in different surgically relevant settings.
