Both sunitinib and sorafenib are effective treatments for pheochromocytoma in a xenograft model

M. Denorme (1) , Laurent Yon (1) , Clément Roux (2) , B.J. J Gonzalez (2) , Emmanuel Baudin (3) , Y. Anouar (1) , C. Dubessy (1)

1 DC2N - Différenciation et communication neuronale et neuroendocrine
2 EnVI - Endothélium, valvulopathies et insuffisance cardiaque
3 IGR - Institut Gustave Roussy

Pheochromocytomas and paragangliomas are rare neuroendocrine tumors which develop from chromaf-fin 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 (40 mg/kg/day) for 14 days 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 suni-tinib and sorafenib reduced the microvessel area (À85% and À80%, respectively) and length (À80% and À78%, respectively) in treated compared to control tumors. In addition, the number of vessel nodes was significantly lower in treated tumors (À95% and À84%, 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 (4 h) 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.

Mots clés: Pheochromocytoma; Xenograft model; Therapy; Angiogenesis; Sorafenib; Sunitinib

Domaines: Sciences du Vivant [q-bio]

M. Denorme, Laurent Yon, Clément Roux, B.J. J Gonzalez, Emmanuel Baudin, et al.. Both sunitinib and sorafenib are effective treatments for pheochromocytoma in a xenograft model. Cancer Letters, 2014, 352 (2), pp.236 - 244. ⟨10.1016/j.canlet.2014.07.005⟩. ⟨hal-01706420⟩