Department of Cancer Biology, Metastasis Research Laboratory, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Transl Oncol. 2012 Feb;5(1):39-47. doi: 10.1593/tlo.11286. Epub 2012 Feb 1.
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.
内皮素受体（ETR）在卵巢肿瘤中常过度表达，这些肿瘤可能对常规治疗产生耐药。因此，我们研究了使用双重 ETR 拮抗剂马西替坦联合紫杉醇或顺铂阻断 ETR 通路是否可以治疗原位生长的多药耐药（MDR）人卵巢癌。在几项研究中，裸鼠被腹腔注射 HeyA8-MDR 人卵巢癌细胞。10 天后，将小鼠随机分为接受载体（生理盐水）、马西替坦（口服，每日）、紫杉醇（腹腔内，每周）、顺铂（腹腔内，每周）、马西替坦加紫杉醇或马西替坦加顺铂。濒死的小鼠被处死，肿瘤被收集、称重并准备进行免疫组织化学分析。HeyA8-MDR 肿瘤对紫杉醇、顺铂或马西替坦单药治疗无反应。相比之下，马西替坦联合紫杉醇或马西替坦联合顺铂联合治疗显著降低了肿瘤发生率和肿瘤重量，并显著延长了小鼠的存活时间和一般状况。多项免疫组织化学分析显示，马西替坦和马西替坦加紫杉醇或顺铂治疗抑制了 ETR 的磷酸化，降低了肿瘤细胞中 pVEGFR2、pAkt 和 pMAPK 的水平，并在治疗 2 周后诱导了肿瘤相关内皮细胞的第一波凋亡，随后是周围肿瘤细胞的凋亡。我们的研究表明，表达内皮素轴且多药耐药的卵巢癌细胞对双重 ET 拮抗剂的治疗极为敏感，可以重新对紫杉醇和顺铂敏感。这种联合治疗导致肿瘤重量显著减轻。
