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Updated: May 24, 2026
Quantitation of Intra-peritoneal Ovarian Cancer Metastasis
Published on: July 18, 2016
Antivascular therapy for multidrug-resistant ovarian tumors by macitentan, a dual endothelin receptor antagonist
Sun-Jin Kim1, Jang Seong Kim, Seung Wook Kim
1Department of Cancer Biology, Metastasis Research Laboratory, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Abstract:
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.
Insights
Dual endothelin receptor antagonist macitentan resensitized multidrug-resistant ovarian cancer to chemotherapy. Combination therapy with macitentan and taxol or cisplatinum significantly reduced tumor growth and improved survival in mice.
Area of Science:
- Oncology
- Pharmacology
- Cancer Biology
Background:
- Endothelin receptors (ETRs) are overexpressed in ovarian tumors, contributing to resistance against conventional therapies.
- Multidrug-resistant (MDR) ovarian carcinoma presents a significant therapeutic challenge.
- Targeting ETR pathways offers a potential strategy to overcome treatment resistance.
Purpose of the Study:
- To investigate the efficacy of the dual ETR antagonist macitentan in combination with taxol or cisplatinum.
- To evaluate the therapeutic potential against orthotopically growing, multidrug-resistant human ovarian carcinoma.
- To determine if macitentan can resensitize resistant ovarian cancer cells to established chemotherapies.
Main Methods:
- Nude mice bearing HeyA8-MDR human ovarian cancer cells were treated with vehicle, macitentan, taxol, cisplatinum, or combinations.
- Tumor incidence, weight, and overall survival were assessed.
- Immunohistochemical analysis was performed to evaluate molecular changes, including ETR phosphorylation, signaling pathways (pVEGFR2, pAkt, pMAPK), and apoptosis.
Main Results:
- Single-agent therapies (macitentan, taxol, cisplatinum) showed no significant response in MDR ovarian tumors.
- Combination therapy with macitentan plus taxol or macitentan plus cisplatinum significantly reduced tumor incidence and weight.
- Combined treatment significantly increased mouse survival and improved their general condition, inhibiting key signaling pathways and inducing apoptosis.
Conclusions:
- Ovarian cancer cells expressing the endothelin axis are sensitive to dual ET antagonist therapy.
- Macitentan resensitizes multidrug-resistant ovarian cancer to taxol and cisplatinum.
- Combined macitentan therapy offers a promising strategy for treating resistant ovarian carcinoma, leading to significant tumor reduction.
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