title: Both sunitinib and sorafenib are effective treatments for pheochromocytoma in a xenograft model.
abstract: Pheochromocytomas and paragangliomas are rare neuroendocrine tumors which develop from chromaffin cells of the adrenal medulla and extra-adrenal sites, leading to excess catecholamine release and hypertension. Many of the tumors are characterized by a high vascularity, suggesting the possible implementation of anti-angiogenic therapies for patients. Here, the efficacy of the tyrosine kinase inhibitors sunitinib and sorafenib was investigated in vivo and in vitro. Oral treatment with either sunitinib or sorafenib (40mg/kg/day) for 14days induced a marked reduction in the volume and weight of PC12 pheochromocytoma cell tumor xenografts in mice. Assessment of tumoral neo-angiogenesis, assessed by morphometric analysis of the vascular network after CD31 immunolabeling, showed that both sunitinib and sorafenib reduced the microvessel area (-85% and -80%, respectively) and length (-80% and -78%, respectively) in treated compared to control tumors. In addition, the number of vessel nodes was significantly lower in treated tumors (-95% and -84%, respectively). Furthermore, cleaved caspase 3 immunolabeling revealed a marked increase in the number of apoptotic cells in tumors from treated animals. Sunitinib and sorafenib could exert a direct effect on PC12 cell viability in vitro. While sunitinib induced a rapid (4h) and pronounced (5-fold) increase in caspase-3/7-dependent apoptosis, sorafenib seems to exert its cytotoxic activity through a different mechanism. Altogether, our data demonstrate that sunitinib and sorafenib have the ability to impair pheochromocytoma development by inhibiting angiogenesis and reducing tumor cell viability. These results strongly suggest that both sunitinib and sorafenib could represent valuable therapeutic tools for pheochromocytoma.
authors.affiliation: Institut National de la Santé et de la Recherche Médicale (INSERM), U982, Mont-Saint-Aignan, France; Normandie Univ, Caen, France; University of Rouen, Laboratory of Neuronal and Neuroendocrine Differentiation and Communication, Institute for Research and Innovation in Biomedicine (IRIB), Mont-Saint-Aignan, France.
authors.forename: M
authors.initials: M
authors.lastname: Denorme
authors.affiliation: Institut National de la Santé et de la Recherche Médicale (INSERM), U982, Mont-Saint-Aignan, France; Normandie Univ, Caen, France; University of Rouen, Laboratory of Neuronal and Neuroendocrine Differentiation and Communication, Institute for Research and Innovation in Biomedicine (IRIB), Mont-Saint-Aignan, France.
authors.forename: L
authors.initials: L
authors.lastname: Yon
authors.affiliation: Normandie Univ, Caen, France; Haute-Normandie-INSERM ERI28, Rouen, France; University of Rouen, Laboratory of Microvascular Endothelium and Neonate Brain Lesion, Institute for Research and Innovation in Biomedicine, Rouen, France.
authors.forename: C
authors.initials: C
authors.lastname: Roux
authors.affiliation: Normandie Univ, Caen, France; Haute-Normandie-INSERM ERI28, Rouen, France; University of Rouen, Laboratory of Microvascular Endothelium and Neonate Brain Lesion, Institute for Research and Innovation in Biomedicine, Rouen, France.
authors.forename: B J
authors.initials: BJ
authors.lastname: Gonzalez
authors.affiliation: Departments of Nuclear Medicine and Endocrine Tumors, Institut Gustave-Roussy, Villejuif, France.
authors.forename: E
authors.initials: E
authors.lastname: Baudin
authors.affiliation: Institut National de la Santé et de la Recherche Médicale (INSERM), U982, Mont-Saint-Aignan, France; Normandie Univ, Caen, France; University of Rouen, Laboratory of Neuronal and Neuroendocrine Differentiation and Communication, Institute for Research and Innovation in Biomedicine (IRIB), Mont-Saint-Aignan, France. Electronic address: youssef.anouar@univ-rouen.fr.
authors.forename: Y
authors.initials: Y
authors.lastname: Anouar
authors.affiliation: Institut National de la Santé et de la Recherche Médicale (INSERM), U982, Mont-Saint-Aignan, France; Normandie Univ, Caen, France; University of Rouen, Laboratory of Neuronal and Neuroendocrine Differentiation and Communication, Institute for Research and Innovation in Biomedicine (IRIB), Mont-Saint-Aignan, France.
authors.forename: C
authors.initials: C
authors.lastname: Dubessy
mesh_terms: D000284:Administration, Oral; D000310:Adrenal Gland Neoplasms / Q000098:blood supply / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D020533:Angiogenesis Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D064593:Heterografts; D007211:Indoles / Q000008:administration & dosage / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic; D009536:Niacinamide / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D016716:PC12 Cells; D010671:Phenylurea Compounds / Q000008:administration & dosage / Q000494:pharmacology*; D010673:Pheochromocytoma / Q000098:blood supply / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D011758:Pyrroles / Q000008:administration & dosage / Q000494:pharmacology*; D051381:Rats; D000077157:Sorafenib; D000077210:Sunitinib; D013997:Time Factors; D047368:Tumor Burden / Q000187:drug effects
chemical_list: D020533:Angiogenesis Inhibitors; D007211:Indoles; D010671:Phenylurea Compounds; D047428:Protein Kinase Inhibitors; D011758:Pyrroles; D009536:Niacinamide; D000077157:Sorafenib; D000077210:Sunitinib
keywords: Angiogenesis; Pheochromocytoma; Sorafenib; Sunitinib; Therapy; Xenograft model