Anthracyclines suppress pheochromocytoma cell characteristics, including metastasis, through inhibition of the hypoxia signaling pathway

// Ying Pang 1 , Chunzhang Yang 2 , Jan Schovanek 3 , Herui Wang 4 , Petra Bullova 5 , Veronika Caisova 1 , Garima Gupta 1 , Katherine I. Wolf 1 , Gregg L. Semenza 6 , Zhengping Zhuang 4 and Karel Pacak 1 1 Section on Medical Neuroendocrinology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland, USA 2 Neuro-Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland, USA 3 Department of Internal Medicine III-Nephrology, Rheumatology, and Endocrinology, Faculty of Medicine and Dentistry, Palacky University, Olomouc, Czech Republic 4 Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland, USA 5 Department of Molecular Medicine, Institute of Virology, Biomedical Research Center, Slovak Academy of Sciences, Bratislava, Slovak Republic 6 McKusick-Nathans Institute of Genetic Medicine and Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA Correspondence to: Karel Pacak, email: // Keywords : anthracyclines, paraganglioma, pheochromocytoma, metastatic, hypoxia-inducible factors Received : January 13, 2017 Accepted : March 03, 2017 Published : March 15, 2017 Abstract Pheochromocytomas (PHEOs) and paragangliomas (PGLs) are rare, neuroendocrine tumors derived from adrenal or extra-adrenal chromaffin cells, respectively. Metastases are discovered in 3-36% of patients at the time of diagnosis. Currently, only suboptimal treatment options exist. Therefore, new therapeutic compounds targeting metastatic PHEOs/PGLs are urgently needed. Here, we investigated if anthracyclines were able to suppress the progression of metastatic PHEO. We explored their effects on experimental mouse PHEO tumor cells using in vitro and in vivo models, and demonstrated that anthracyclines, particularly idarubicin (IDA), suppressed hypoxia signaling by preventing the binding of hypoxia-inducible factor 1 and 2 (HIF-1 and HIF-2) to the hypoxia response element (HRE) sites on DNA. This resulted in reduced transcriptional activation of HIF target genes, including erythropoietin ( EPO ), phosphoglycerate kinase 1 ( PGK1 ), endothelin 1 ( EDN1 ), glucose transporter 1 ( GLUT1 ), lactate dehydrogenase A ( LDHA ), and vascular endothelial growth factor ( VEGFA ), which consequently inhibited the growth of metastatic PHEO. Additionally, IDA downregulated hypoxia signaling by interfering with the transcriptional activation of HIF1A and HIF2A . Furthermore, our animal model demonstrated the dose-dependent suppressive effect of IDA on metastatic PHEO growth in vivo . Our results indicate that anthracyclines are prospective candidates for inclusion in metastatic PHEO/PGL therapy, especially in patients with gene mutations involved in the hypoxia signaling pathway.