title: Macitentan (ACT-064992), a tissue-targeting endothelin receptor antagonist, enhances therapeutic efficacy of paclitaxel by modulating survival pathways in orthotopic models of metastatic human ovarian cancer.
abstract: 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.
authors.affiliation: Department of Cancer Biology, Cancer Metastasis Research Center, The University of Texas, MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Sun-Jin
authors.initials: SJ
authors.lastname: Kim
authors.forename: Jang Seong
authors.initials: JS
authors.lastname: Kim
authors.forename: Seung Wook
authors.initials: SW
authors.lastname: Kim
authors.forename: Emily
authors.initials: E
authors.lastname: Brantley
authors.forename: Seok Joong
authors.initials: SJ
authors.lastname: Yun
authors.forename: Junqin
authors.initials: J
authors.lastname: He
authors.forename: Marva
authors.initials: M
authors.lastname: Maya
authors.forename: Fahao
authors.initials: F
authors.lastname: Zhang
authors.forename: Qiuyu
authors.initials: Q
authors.lastname: Wu
authors.forename: François
authors.initials: F
authors.lastname: Lehembre
authors.forename: Urs
authors.initials: U
authors.lastname: Regenass
authors.forename: Isaiah J
authors.initials: IJ
authors.lastname: Fidler
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols; D065128:Endothelin Receptor Antagonists; D005260:Female; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000473:pathology*; D017239:Paclitaxel / Q000627:therapeutic use*; D010534:Peritoneal Neoplasms / Q000517:prevention & control / Q000556:secondary; D011743:Pyrimidines / Q000008:administration & dosage / Q000627:therapeutic use*; D013449:Sulfonamides / Q000008:administration & dosage / Q000627:therapeutic use*; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: D065128:Endothelin Receptor Antagonists; D011743:Pyrimidines; D013449:Sulfonamides; D017239:Paclitaxel; C533860:macitentan