TY - JOUR
T1 - Antivascular therapy for multidrug-resistant ovarian tumors by macitentan, a dual endothelin receptor antagonist
AU - Kim, Sun Jin
AU - Kim, Jang Seong
AU - Kim, Seung Wook
AU - Yun, Seok Joong
AU - He, Junqin
AU - Brantley, Emily
AU - Fan, Dominic
AU - Strickner, Panja
AU - Lehembre, François
AU - Regenass, Urs
AU - Fidler, Isaiah J.
N1 - Funding Information:
Address all correspondence to: Isaiah J. Fidler, Department of Cancer Biology, Metastasis Research Laboratory, Unit 854, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030. E-mail: ifidler@mdanderson.org 1This work was supported in part by Cancer Center Support Core grant CA16672 and grant 1U54CA143837-01 from the National Cancer Institute, National Institutes of Health, and by sponsored research from Actelion Pharmaceuticals, Ltd. There is no conflict of interest with any author or product used in this translational research study. 2These authors contributed equally to this work. Received 3 October 2011; Revised 3 October 2011; Accepted 20 October 2011 Copyright © 2012 Neoplasia Press, Inc. Open access under CC BY-NC-ND license. 1944-7124/12 DOI 10.1593/tlo.11286
PY - 2012/2
Y1 - 2012/2
N2 - 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.
AB - 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.
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U2 - 10.1593/tlo.11286
DO - 10.1593/tlo.11286
M3 - Article
C2 - 22348175
AN - SCOPUS:84862961320
SN - 1944-7124
VL - 5
SP - 39
EP - 47
JO - Translational Oncology
JF - Translational Oncology
IS - 1
ER -