title: Macitentan blocks endothelin-1 receptor activation required for chemoresistant ovarian cancer cell plasticity and metastasis.
abstract: OBJECTIVE
  In epithelial ovarian cancer (EOC), activation of endothelin-1 (ET-1)/endothelin A receptor (ETAR) and ET-1/ETBR signaling is linked to many tumor promoting effects, such as proliferation, angiogenesis, invasion, metastasis and chemoresistance. Understanding how to hamper the distinct mechanisms that facilitate epithelial plasticity and propagation is therefore central for improving the clinical outcome for EOC patients.
  
  
  METHODS
  The phosphorylation status of Akt and MAPK was evaluated by immunoblotting in A2780 and 2008 EOC cell lines and their cisplatinum-resistant variants. Vasculogenic mimicry was analyzed by vascular tubules formation assay. Tumor growth and metastases inhibition was performed in chemoresistant EOC xenografts.
  
  
  RESULTS
  We found that the dual ETAR/ETBR antagonist macitentan was able to inhibit the ET-1-induced activation of Akt and MAPK signaling pathways in chemoresistant EOC cells. Moreover, chemoresistant EOC cells displayed higher capability to engage vasculogenic mimicry compared to sensitive cells that was inhibited after treatment with macitentan. Finally, the specific ETAR antagonist zibotentan was less efficacious compared to macitentan to suppress tumor growth in chemoresistant EOC xenografts and the co-treatment of macitentan and cisplatinum reduced the metastatic progression.
  
  
  CONCLUSIONS
  Our findings better clarify the ET-1-induced molecular mechanisms underlying the aggressive behavior of chemoresistant EOC cells. These results also support the use of macitentan in combination with chemotherapy as a rational therapeutic strategy for circumventing drug resistance in EOC.
authors.affiliation: Translational Research Functional Departmental Area, Regina Elena National Cancer Institute, Rome, Italy.
authors.forename: Rosanna
authors.initials: R
authors.lastname: Sestito
authors.affiliation: Translational Research Functional Departmental Area, Regina Elena National Cancer Institute, Rome, Italy.
authors.forename: Roberta
authors.initials: R
authors.lastname: Cianfrocca
authors.affiliation: Translational Research Functional Departmental Area, Regina Elena National Cancer Institute, Rome, Italy.
authors.forename: Laura
authors.initials: L
authors.lastname: Rosanò
authors.affiliation: Translational Research Functional Departmental Area, Regina Elena National Cancer Institute, Rome, Italy.
authors.forename: Piera
authors.initials: P
authors.lastname: Tocci
authors.affiliation: Translational Research Functional Departmental Area, Regina Elena National Cancer Institute, Rome, Italy.
authors.forename: Valeriana
authors.initials: V
authors.lastname: Di Castro
authors.affiliation: Translational Research Functional Departmental Area, Regina Elena National Cancer Institute, Rome, Italy.
authors.forename: Valentina
authors.initials: V
authors.lastname: Caprara
authors.affiliation: Translational Research Functional Departmental Area, Regina Elena National Cancer Institute, Rome, Italy. Electronic address: bagnato@ifo.it.
authors.forename: Anna
authors.initials: A
authors.lastname: Bagnato
mesh_terms: D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D009362:Neoplasm Metastasis; D010051:Ovarian Neoplasms / Q000473:pathology*; D011743:Pyrimidines / Q000494:pharmacology*; D044022:Receptor, Endothelin A / Q000187:drug effects*; D013449:Sulfonamides / Q000494:pharmacology*
chemical_list: D011743:Pyrimidines; D044022:Receptor, Endothelin A; D013449:Sulfonamides; C533860:macitentan
keywords: Chemoresistance; Endothelin-1; Macitentan; Ovarian carcinoma; Vasculogenic mimicry