Endothelin receptor antagonists in the treatment of prostate cancer

Lassiter, Lance K.; Carducci, Michael A.

doi:10.1016/s0093-7754(03)00353-1

Cited by 31 publications

(15 citation statements)

References 54 publications

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“…(39) Similar antitumoral effects have been achieved in prostate and cervical cancer. (40,41) The present study showed that ET-1 is produced by all three of the NPC cell lines used, and mRNA expression of ET A R is limited to some cell lines (SUNE-1 and HONE-1, not CNE-2).…”

Section: Discussionmentioning

confidence: 58%

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: 58%

Therapeutic targeting of the endothelin a receptor in human nasopharyngeal carcinoma

Qiang

Zeng²,

Feng³

et al. 2006

Cancer Science

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“…Therefore, the use of endothelin receptor antagonists, including bosentan, as anticancer drugs has been addressed in experimental and clinical settings (25)(26)(27)(28).…”

Section: Discussionmentioning

confidence: 99%

The Endothelin Receptor Blocker Bosentan Inhibits Doxorubicin-Induced Cardiomyopathy

et al. 2007

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Doxorubicin is a frequently used anticancer drug, but its therapeutic benefit is limited by acute and chronic cardiotoxicity, often leading to heart failure. The mechanisms underlying doxorubicin-induced cardiotoxicity remain unclear. It was previously shown in men that doxorubicin leads to increased endothelin-1 plasma levels. In addition, cardiacspecific overexpression of endothelin-1 in mice resulted in a cardiomyopathy resembling the phenotype following doxorubicin administration. We therefore hypothesized that endothelin-1 is involved in the pathogenesis of doxorubicin cardiotoxicity. In mice (C57Bl/10), we found that doxorubicin (20 mg/kg body weight, i.p.) impaired cardiac function with decreased ejection fraction, diminished cardiac output, and decreased end-systolic pressure points recorded by a microconductance catheter. This impaired function was accompanied by the up-regulation of endothelin-1 expression on mRNA and protein level. In vitro investigations confirmed the regulation of endothelin-1 by doxorubicin and indicated that the doxorubicin-mediated increase of endothelin-1 expression involves epidermal growth factor receptor signaling via the MEK1/2-ERK1/2 cascade, which was further confirmed by immunoblotting studies in the left ventricle of treated animals. Pretreatment of mice with the endothelin receptor antagonist bosentan (100 mg/kg body weight, p.o.) strikingly inhibited doxorubicin-induced cardiotoxicity with preserved indices of contractility. Moreover, bosentan pretreatment resulted in reduced tumor necrosis factor-A content, lipid peroxidation, and Bax expression, as well as increased GATA-4 expression. Thus, endothelin-1 plays a key role in mediating the cardiotoxic effects of doxorubicin and its inhibition may be of therapeutic benefit for patients receiving doxorubicin.

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“…Endothelin-1 receptor agonists are currently being tested in clinical trials. Statistical improvements have been reported with regard to bone pain levels, serum PSA levels, biologic bone markers of bone changes and bone metastases [36].…”

Section: Osteoblastic Bone Metastasismentioning

confidence: 99%

Mechanisms of cancer metastasis to the bone

Yin¹,

Pollock²,

Kelly³

2005

Cell Res

296

226

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Some of the most common human cancers, including breast cancer, prostate cancer, and lung cancer, metastasize with avidity to bone. What is the basis for their preferential growth within the bone microenvironment? Bidirectional interactions between tumor cells and cells that make up bone result in a selective advantage for tumor growth and can lead to bone destruction or new bone matrix deposition. This review discusses our current understanding of the molecular components and mechanisms that are responsible for those interactions.

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Endothelin receptor antagonists in the treatment of prostate cancer

Cited by 31 publications

References 54 publications

Therapeutic targeting of the endothelin a receptor in human nasopharyngeal carcinoma

Therapeutic targeting of the endothelin a receptor in human nasopharyngeal carcinoma

The Endothelin Receptor Blocker Bosentan Inhibits Doxorubicin-Induced Cardiomyopathy

Mechanisms of cancer metastasis to the bone

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