Hypoxia potentiates the cytotoxic effect of piperlongumine in pheochromocytoma models

// Petra Bullova 1, 2, * , Antony Cougnoux 3, * , Luma Abunimer 1 , Juraj Kopacek 2 , Silvia Pastorekova 2 , Karel Pacak 1 1 Section on Medical Neuroendocrinology, Eunice Kennedy Shriver NICHD, NIH, Bethesda, MD, 20892, USA 2 Department of Molecular Medicine, Institute of Virology, Biomedical Research Center, Slovak Academy of Sciences, 84505 Bratislava, Slovakia 3 Section on Molecular Dysmorphology, Eunice Kennedy Shriver NICHD, NIH, Bethesda, MD, 20892, USA * These authors have contributed equally to this work Correspondence to: Karel Pacak, email: mailto:karel@mail.nih.gov Keywords: pheochromocytoma, piperlongumine, hypoxia, reactive-oxygen species, apoptosis Received: January 12, 2016     Accepted: April 23, 2016     Published: May 26, 2016 ABSTRACT Hypoxia is a common feature of solid tumors that activates a plethora of pathways, resulting in proliferation and resistance of cancer cells to radio- and chemotherapy. Pheochromocytomas/paragangliomas (PHEOs/PGLs) with mutations in the gene coding for the subunit B of succinate dehydrogenase ( SDHB ) are the most aggressive forms of the disease, which is partially due to their pseudohypoxic character, metabolic abnormalities, and elevated reactive oxygen species (ROS) levels. We investigated the effect of piperlongumine (PL), a natural product with cytotoxic properties restricted to cancer cells by significantly increasing intracellular ROS levels, on PHEO cells. Here we report for the first time that PL mediates PHEO cell death by activating both apoptosis and necroptosis in vitro and in vivo . This effect is magnified in hypoxic conditions, making PL a promising potential candidate for use as a therapeutic option for patients with PHEO/PGL, including those with SDHB mutations.