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Prolyl Hydroxylase Inhibition Enhances Liver Regeneration Without Induction of Tumor Growth

Harnoss, Jonathan M. MD; Platzer, Lisa K.; Burhenne, Juergen PhD; Radhakrishnan, Praveen MSc; Cai, Jun; Strowitzki, Moritz J. MD; Weiss, Johanna PhD; Ritter, Alina Sophia; Mollenhauer, Martin PhD; Schmidt, Thomas MD, PhD; Ulrich, Alexis MD; Haefeli, Walter Emil MD; Schneider, Martin MD

doi: 10.1097/SLA.0000000000001696
Original Articles

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.

*Department of General, Visceral and Transplantation Surgery, University of Heidelberg, Heidelberg, Germany

Department of Clinical Pharmacology and Pharmacoepidemiology, University of Heidelberg, Heidelberg, Germany.

Reprints: Martin Schneider, MD, Department of General, Visceral and Transplantation Surgery, University of Heidelberg, Im Neuenheimer Feld 110, D-69120 Heidelberg, Germany. E-mail: m.schneider@uni-heidelberg.de.

J.M.H. and L.K.P. contributed equally to this work.

Source of funding: This study was supported in the framework of the Clinical Research Group KFO 227 by the Deutsche Forschungsgemeinschaft, Germany.

Disclosure: The author reports no conflicts of interest.

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