Potential treatments for ovarian cancers that have become resistant to standard 
chemotherapies include modulators of tumor cell survival, such as endothelin 
receptor (ETR) antagonist. We investigated the therapeutic efficacy of the dual 
ETR antagonist, macitentan, on human ovarian cancer cells, SKOV3ip1 and IGROV1, 
growing orthotopically in nude mice. Mice with established disease were treated 
with vehicle (control), paclitaxel (weekly, intraperitoneal injections), 
macitentan (daily oral administrations), or a combination of paclitaxel and 
macitentan. Treatment with paclitaxel decreased tumor weight and volume of 
ascites. Combination therapy with macitentan and paclitaxel reduced tumor 
incidence and further reduced tumor weight and volume of ascites when compared 
with paclitaxel alone. Macitentan alone occasionally reduced tumor weight but 
alone had no effect on tumor incidence or ascites. Immunohistochemical analyses 
revealed that treatment with macitentan and macitentan plus paclitaxel inhibited 
the phosphorylation of ETRs and suppressed the survival pathways of tumor cells 
by decreasing the levels of pVEGFR2, pAkt, and pMAPK. The dose of macitentan 
necessary for inhibition of phosphorylation correlated with the dose required to 
increase antitumor efficacy of paclitaxel. Treatment with macitentan enhanced 
the cytotoxicity mediated by paclitaxel as measured by the degree of apoptosis 
in tumor cells and tumor-associated endothelial cells. Collectively, these 
results show that administration of macitentan in combination with paclitaxel 
prevents the progression of ovarian cancer in the peritoneal cavity of nude mice 
in part by inhibiting survival pathways of both tumor cells and tumor-associated 
endothelial cells.