Inhibiting Endothelin Receptors with Macitentan Strengthens the Bone Protective Action of RANKL Inhibition and Reduces Metastatic Dissemination in Osteosarcoma

Cancers

Jorge William Vargas-Franco¹  Marie-Françoise Heymann²  Dominique Heymann²  Javier Muñoz-Garcia²  Denis Cochonneau²  Bénédicte Brounais-Le Royer³  Jérôme Amiaud³  Frédéric Lézot⁴ 

[1] Department of Basic Studies, Faculty of Odontology, University of Antioquia, Medellin 53-108, Colombia;Institut de Cancérologie de l’Ouest, F-44805 Saint-Herblain, France;Nantes Université, F-44000 Nantes, France;Sorbonne Université, INSERM, UMR933, Hôpital Trousseau (AP-HP), F-75012 Paris, France;

关键词: osteosarcoma;    RANKL;    endothelin;    bone protection;    metastases;   

DOI  :  10.3390/cancers14071765

来源: DOAJ

【 摘 要 】

Current treatments for osteosarcoma, combining conventional polychemotherapy and surgery, make it possible to attain a five-year survival rate of 70% in affected individuals. The presence of chemoresistance and metastases significantly shorten the patient’s lifespan, making identification of new therapeutic tools essential. Inhibiting bone resorption has been shown to be an efficient adjuvant strategy impacting the metastatic dissemination of osteosarcoma, tumor growth, and associated bone destruction. Unfortunately, over-apposition of mineralized matrix by normal and tumoral osteoblasts was associated with this inhibition. Endothelin signaling is implicated in the functional differentiation of osteoblasts, raising the question of the potential value of inhibiting it alone, or in combination with bone resorption repression. Using mouse models of osteosarcoma, the impact of macitentan, an endothelin receptor inhibitor, was evaluated regarding tumor growth, metastatic dissemination, matrix over-apposition secondary to RANKL blockade, and safety when combined with chemotherapy. The results showed that macitentan has no impact on tumor growth or sensitivity to ifosfamide, but significantly reduces tumoral osteoid tissue formation and the metastatic capacity of the osteosarcoma. To conclude, macitentan appears to be a promising therapeutic adjuvant for osteosarcoma alone or associated with bone resorption inhibitors.

【 授权许可】

Unknown