• 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, and Martin Schneider.
• *Department of General, Visceral and Transplantation Surgery, University of Heidelberg, Heidelberg, Germany †Department of Clinical Pharmacology and Pharmacoepidemiology, University of Heidelberg, Heidelberg, Germany.
• Ann. Surg. 2017 Apr 1; 265 (4): 782-791.

ObjectiveWe 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).BackgroundLiver 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.MethodsVarious 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.ResultsEDHB 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.ConclusionsPharmacological inhibition of PHDs using EDHB might represent a novel and safe strategy in the treatment of multiple bilobar CRLM.

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