Prolyl Hydroxylase Inhibition Enhances Liver Regeneration Without Induction of Tumor Growth.

Abstract

OBJECTIVE:

We sought to assess whether pharmacological inhibition of hypoxia-inducible transcription factor (HIF)-prolyl hydroxylase enzymes (PHD1, PHD2, and PHD3) is a suitable strategy to stimulate liver regeneration after partial hepatectomy for colorectal liver metastases (CRLM).

BACKGROUND:

Liver regeneration occurs in a hypoxic environment. PHD1 to PHD3 are molecular oxygen sensors and increasingly considered as putative therapeutic targets. However, little is known about the effect of pharmacological PHD inhibition on tumor expansion, and on liver regeneration after surgical resection.

METHODS:

Various mouse models of liver regeneration after extended partial hepatectomy and portal vein ligation for multiple bilobar CRLM were applied to assess the effect of the small molecule pan-PHD inhibitor ethyl-3,4-dihydroxybenzoate (EDHB) on liver regeneration and metastatic tumor growth. Metabolism and biodistribution of EDHB were analyzed using liquid chromatography coupled to tandem mass spectrometry.

RESULTS:

EDHB selectively augmented liver regeneration after partial hepatectomy and portal vein ligation, and increased the expression of cell cycle-promoting cyclin proteins, without enhancing metastatic tumor growth. Systemically administered EDHB and its active metabolite 3,4-dihydroxybenzoic acid accumulated in the liver to selectively induce hepatoprotective effects in the liver, but not in tumor tissue, without humoral adverse effects.

CONCLUSIONS:

Pharmacological inhibition of PHDs using EDHB might represent a novel and safe strategy in the treatment of multiple bilobar CRLM.

• Authors: Jonathan M Harnoss, Lisa K Platzer, Juergen Burhenne, Praveen Radhakrishnan, Jun Cai, Moritz J Strowitzki, Johanna Weiss, Alina Sophia Ritter, Martin Mollenhauer, Thomas Schmidt, Alexis Ulrich, Walter Emil Haefeli, Martin Schneider
• Journal: Annals of surgery (Ann Surg) Vol. 265 Issue 4 Pg. 782-791 (04 2017) ISSN: 1528-1140 [Electronic] United States
• PMID: 28266966 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Hypoxia-Inducible Factor 1, alpha Subunit
• Prolyl-Hydroxylase Inhibitors

Topics

• Analysis of Variance
• Animals
• Blotting, Western
• Colorectal Neoplasms (pathology, surgery)
• Disease Models, Animal
• Female
• Hepatectomy (methods)
• Hypoxia-Inducible Factor 1, alpha Subunit (metabolism)
• Liver Neoplasms (secondary, surgery)
• Liver Regeneration (drug effects)
• Mice
• Mice, Inbred BALB C
• Prolyl-Hydroxylase Inhibitors (pharmacology)
• Random Allocation
• Real-Time Polymerase Chain Reaction
• Sensitivity and Specificity
• Tumor Cells, Cultured (drug effects)