Expression of Endothelin Receptor a Associated With Prostate Cancer Progression

Gohji, Kazuo; Kitazawa, Sohei; Tamada, Hiroshi; Katsuoka, Yoji; Nakajima, Motowo

doi:10.1016/s0022-5347(05)66597-4

Cited by 110 publications

(63 citation statements)

References 15 publications

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“…In cancer of the prostate and breast, ET A R overexpression is associated with aggressive tumor behavior and a worse prognosis. (30,31) In our previous study, (23) ET A R expression was found in 73.9% of patients with NPC. Correlative analysis showed that ET A R expression was a strong, independent prognostic indicator of overall survival and relapse-free survival rate.…”

Section: Discussionmentioning

confidence: 88%

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Therapeutic targeting of the endothelin a receptor in human nasopharyngeal carcinoma

Qiang

Zeng²,

Feng³

et al. 2006

Cancer Science

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The endothelin A receptor (ET A R) autocrine pathway is overexpressed in many malignancies, including nasopharyngeal carcinoma (NPC). In this tumor, ET A R expression is an independent determinant of survival and a robust independent predictor of distant metastasis. To evaluate whether ET A R represents a new target in NPC treatment, we tested the therapeutic role of ET A R in NPC. N asopharyngeal carcinoma is common in Southern China, with an annual incidence of 15-50 cases per 100 000 people.(1) NPC is distinct from other epithelial malignancies in the head and neck region in that it affects a relatively young population and has a propensity for distant metastases.(2) NPC is a radiosensitive tumor for which there is a high local control rate after radical radiotherapy. However, for patients with locoregionally advanced disease, the rate of distant metastasis is high and the 5-year overall survival rate is poor.(3) Randomized trials have confirmed that chemotherapy improves the distant metastasis control rate in patients with locoregionally advanced NPC; however, approximately 20% or more of the patients still have distant metastasis develop despite intensive chemotherapy.(4,5) These findings underscore the need to develop novel strategies in the management of patients with advanced NPC.The family of ET, including ET-1, ET-2 and ET-3, are 21-amino acid peptides exerting many biological effects.(6) Two major receptor subtypes belonging to the G protein-coupled family of receptors mediate ET signals: ET A R, which binds ET-1 and ET-2 with high affinity and ET-3 with low affinity; and ET B R, which binds all ET isopeptides with equal affinity.(7) ET-1, which is the most common circulating form of ET, is produced by many epithelial tumors.(8) ET-1 induces cell proliferation directly or synergistically with other growth factors that are relevant in cancer progression. Engagement of ET A R by ET-1 triggers activation of tumor proliferation, (9-13) VEGF-induced angiogenesis, (14,15) invasiveness (16) and inhibition of apoptosis. (17,18) The ET-1-ET A R autocrine pathway has a key role in the development and progression of prostatic, ovarian and cervical cancers.(9) The major relevance of ET A R in tumor development has led to an extensive search of highly selective antagonists. ABT-627 (Atrasentan), one such antagonist, is orally bioavailable and has suitable pharmacokinetic and toxicity profiles for clinical use. (19,20) ABT-627 has been given to cancer patients in phase II trials for prostate cancer and delayed the time to clinical and prostate-specific antigen progression.(21) Two pivotal randomized, double-blind, placebo-controlled, multinational phase III trials are ongoing in patients with hormone-refractory prostate cancer to verify these findings.We reported previously that patients with advanced-stage NPC had elevated plasma big ET-1 levels compared with the levels in healthy control participants; high pretreatment plasma big ET-1 levels are generally associated with post-treatment distant failure.(22) Our pr...

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Section: Discussionmentioning

confidence: 88%

“…Increased ET A R expression has been reported in a broad range of human cancers, including prostate, (30) ovarian, (12) breast, (31) colon, (32) lung, (33) cervical, (13) renal (34) and thyroid gland. (35) Overexpression of ET A R is generally associated with a more malignant phenotype.…”

Section: Discussionmentioning

confidence: 99%

Therapeutic targeting of the endothelin a receptor in human nasopharyngeal carcinoma

Qiang

Zeng²,

Feng³

et al. 2006

Cancer Science

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“…The ET A R has been reported as a new therapeutic target in several human cancers, including cervical (32), prostate (33), ovarian (21), breast (34), colon (35), lung (36), renal (37), and thyroid gland (38) malignancies. ET A R signaling has been shown convincingly to regulate stromal-tumor cell interactions promoting tumor growth, neovascularization, and metastatic spread (3,11,12,39).…”

Section: Discussionmentioning

confidence: 99%

ZD4054, a specific antagonist of the endothelin A receptor, inhibits tumor growth and enhances paclitaxel activity in human ovarian carcinoma in vitro and in vivo

Rosanò

Castro

Spinella

et al. 2007

Molecular Cancer Therapeutics

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The autocrine endothelin (ET)-1/endothelin A receptor (ET A R) pathway is an important regulator of several processes involved in ovarian cancer progression, and its overexpression is associated with aggressive disease. These features have led to the proposal of the ET A R receptor as a potential target for improving ovarian cancer treatment. In this study, we evaluated in vitro and in vivo the effects of ZD4054, an orally active antagonist that specifically binds ET A R, as monotherapy, and in combination with paclitaxel. In the human ovarian cancer ET A Rpositive cell lines HEY, OVCA 433, SKOV-3, and A-2780, ZD4054 effectively inhibited the basal and ET-1 -induced cell proliferation, associated with the inhibition of AKT and p42/44MAPK phosphorylation, and with increased apoptosis, through the inhibition of bcl-2 and activation of caspase-3 and poly(ADP-ribose) polymerase proteins. ZD4054 treatment also resulted in a reduction of ET A Rdriven angiogenesis and invasive mediators, such as vascular endothelial growth factor, cyclooxygenase-1/2, and matrix metalloproteinase (MMP). The combination of ZD4054 and paclitaxel led to the potentiation of all these effects, indicating that ZD4054, by blocking the ET A R-dependent proliferative, invasive, and antiapoptotic signals, can enhance sensitivity to paclitaxel. In HEY ovarian cancer xenografts, ZD4054 significantly inhibited tumor growth to the same degree as paclitaxel. Furthermore, ZD4054-dependent tumor growth inhibition was associated with a reduction in proliferation index, microvessel density, and MMP-2 expression. Interestingly, the combination of ZD4054 and paclitaxel produced additive antitumor effects, with 40% of mice remaining tumorfree, supporting a rationale for the clinical use of ZD4054 as monotherapy or in combination with cytotoxic drugs.

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“…Elevated plasma levels of ET-1 have also been detected in patients with various solid tumors, including hepatocellular [8] and colorectal [9] cancers. Furthermore, increased ET-A expression in malignant tissue has been demonstrated in several cancer types, including breast [10], ovarian [11], and advanced prostate [12] cancer. The engagement of ET-A by ET-1 is known to trigger activation of tumor growth [13], VEGF-induced angiogenesis [11], cancer cell invasiveness [14], and inhibition of apoptosis [15].…”

Section: Discussionmentioning

confidence: 99%

Inhibitory effect of endothelin A receptor blockade on tumor growth and liver metastasis of a human gastric cancer cell line

et al. 2007

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study, to determine the metastasis-related genes of gastric cancer, we analyzed the differential gene expression of established human gastric cancer cell lines -AZH5c, a highly liver metastatic cell line; AZ-P7a, a cell line with high peritoneal dissemination; AZ-L5G, a highly lymph node metastatic cell line -and compared the fi ndings with those from AZ-521, a parental low metastatic cell line. The results revealed that the ET-A gene was the only one of three highly metastatic cell lines that was generally up-regulated, in contrast to the AZ-521 line. Thus, we evaluated the possibility that ET-A might play an important role in the mechanism of gastric cancer metastasis and that the ET-A blockade could have an antimetastatic effect. We conducted in vitro and in vivo experiments using a non-peptideselective ET-A antagonist, YM598 (Astellas Pharma, Tokyo, Japan). The present study demonstrates the inhibitory effect of ET-A blockade on the cell proliferation, tumor growth, and liver metastasis of gastric cancer. Materials and methods AnimalsAthymic female BALB/c nu/nu mice used; they were 5-7 weeks old and weighed 20-22 g. They originated from the Central Institute for Experimental Animals (Kawasaki, Japan) and were purchased from Clea Japan (Tokyo, Japan). The mice were maintained in a laminar airfl ow cabinet under specifi c pathogen-free conditions and were provided with sterile food and water. All experiments were performed according to institutional ethical guidelines on animal care. Results. An in vivo study using nude mice demonstrated that YM598 had a signifi cant growth inhibition effect on AZ-H5c at doses of 0.5-10.0 mg/kg. The liver metastatic rate was also signifi cantly reduced by YM598: control, 83.3%; 1 mg/kg dosage, 16.7%; 10 mg/kg, 20%; and pretreatment at 1 mg/kg, 16.7%. There was no evidence of gross toxicity resulting from the YM598 treatment. Conclusion. The ET-A blockade by YM598 had a strong inhibitory effect against tumor growth and liver metastasis of the gastric cancer cell lines. These data suggest that YM598 has potential as a novel therapeutic agent for inhibiting liver metastasis of gastric cancer. Cell lines and cell culture

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Expression of Endothelin Receptor a Associated With Prostate Cancer Progression

Abstract: Our results indicate that endothelin receptor A expression may serve as a marker for and have an important role in prostate cancer progression.

Cited by 110 publications

References 15 publications

Therapeutic targeting of the endothelin a receptor in human nasopharyngeal carcinoma

Therapeutic targeting of the endothelin a receptor in human nasopharyngeal carcinoma

ZD4054, a specific antagonist of the endothelin A receptor, inhibits tumor growth and enhances paclitaxel activity in human ovarian carcinoma in vitro and in vivo

Inhibitory effect of endothelin A receptor blockade on tumor growth and liver metastasis of a human gastric cancer cell line

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