Endothelin receptors (ETRs) are often overexpressed in ovarian tumors, which can 
be resistant to conventional therapies. Thus, we investigated whether blockage 
of the ETR pathways using the dual ETR antagonist macitentan combined with taxol 
or cisplatinum can produce therapy for orthotopically growing 
multidrug-resistant (MDR) human ovarian carcinoma. In several studies, nude mice 
were injected in the peritoneal cavity with HeyA8-MDR human ovarian cancer 
cells. Ten days later, mice were randomized to receive vehicle (saline), 
macitentan (oral, daily), taxol (intraperitoneal, weekly), cisplatinum 
(intraperitoneal, weekly), macitentan plus taxol, or macitentan plus 
cisplatinum. Moribund mice were killed, and tumors were collected, weighed, and 
prepared for immunohistochemical analysis. The HeyA8-MDR tumors did not respond 
to taxol, cisplatinum, or macitentan administered as single agents. In contrast, 
combination therapy with macitentan and taxol or macitentan and cisplatinum 
significantly decreased the tumor incidence and weight and significantly 
increased the survival of mice and their general condition. Multiple 
immunohistochemical analyses revealed that treatment with macitentan and 
macitentan plus taxol or cisplatinum inhibited the phosphorylation of ETRs, 
decreased the levels of pVEGFR2, pAkt, and pMAPK in tumor cells after 2 weeks of 
treatment and induced a first wave of apoptosis in tumor-associated endothelial 
cells followed by apoptosis in surrounding tumor cells. Our study shows that 
ovarian cancer cells, which express the endothelin axis and are multidrug 
resistant, are exquisitely sensitive to treatment with a dual ET antagonist and 
can be resensitized to both taxol and cisplatinum. This combined therapy led to 
a significant reduction in tumor weight.