title: Hypoxia potentiates the cytotoxic effect of piperlongumine in pheochromocytoma models.
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.
authors.affiliation: Section on Medical Neuroendocrinology, Eunice Kennedy Shriver NICHD, NIH, Bethesda, MD, 20892, USA.|Department of Molecular Medicine, Institute of Virology, Biomedical Research Center, Slovak Academy of Sciences, 84505 Bratislava, Slovakia.
authors.forename: Petra
authors.initials: P
authors.lastname: Bullova
authors.affiliation: Section on Molecular Dysmorphology, Eunice Kennedy Shriver NICHD, NIH, Bethesda, MD, 20892, USA.
authors.forename: Antony
authors.initials: A
authors.lastname: Cougnoux
authors.affiliation: Section on Medical Neuroendocrinology, Eunice Kennedy Shriver NICHD, NIH, Bethesda, MD, 20892, USA.
authors.forename: Luma
authors.initials: L
authors.lastname: Abunimer
authors.affiliation: Department of Molecular Medicine, Institute of Virology, Biomedical Research Center, Slovak Academy of Sciences, 84505 Bratislava, Slovakia.
authors.forename: Juraj
authors.initials: J
authors.lastname: Kopacek
authors.affiliation: Department of Molecular Medicine, Institute of Virology, Biomedical Research Center, Slovak Academy of Sciences, 84505 Bratislava, Slovakia.
authors.forename: Silvia
authors.initials: S
authors.lastname: Pastorekova
authors.affiliation: Section on Medical Neuroendocrinology, Eunice Kennedy Shriver NICHD, NIH, Bethesda, MD, 20892, USA.
authors.forename: Karel
authors.initials: K
authors.lastname: Pacak
mesh_terms: D000310:Adrenal Gland Neoplasms / Q000188:drug therapy* / Q000235:genetics; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis; D016923:Cell Death; D045744:Cell Line, Tumor; D002465:Cell Movement; D002470:Cell Survival; D004148:Dioxolanes / Q000494:pharmacology*; D005260:Female; D006801:Humans; D000860:Hypoxia; D051379:Mice; D008819:Mice, Nude; D009361:Neoplasm Invasiveness; D010084:Oxidation-Reduction; D010235:Paraganglioma / Q000188:drug therapy* / Q000235:genetics; D010673:Pheochromocytoma / Q000188:drug therapy* / Q000235:genetics; D034741:RNA, Small Interfering / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D013385:Succinate Dehydrogenase / Q000235:genetics; D010881:Piperidones
chemical_list: D000970:Antineoplastic Agents; D004148:Dioxolanes; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; D013385:Succinate Dehydrogenase; C108095:SDHB protein, human; C498077:piperlongumine; D010881:Piperidones
keywords: apoptosis; hypoxia; pheochromocytoma; piperlongumine; reactive-oxygen species