CGS 35601, a Triple Inhibitor of Angiotensin Converting Enzyme, Neutral Endopeptidase and Endothelin Converting Enzyme

Battistini, Bruno; Daull, Philippe; Jeng, Arco Y.

doi:10.1111/j.1527-3466.2005.tb00175.x

Cited by 34 publications

(17 citation statements)

References 45 publications

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“…Alternatively, the enzymatic activity of CD10 could promote tumor growth by conversion of a propeptide into a biologically active, stimulatory form. These (25,26) may be applied to counteract the unfavorable effects of CD10 on survival. Second, CD10 can process peptide prodrugs, increasing their cytotoxic potency on CD10-expressing tumor cells 100-to 300-fold (27).…”

Section: Discussionmentioning

confidence: 99%

Distinct Subcellular Expression Patterns of Neutral Endopeptidase (CD10) in Prostate Cancer Predict Diverging Clinical Courses in Surgically Treated Patients

Fleischmann

Schlomm²,

Huland

et al. 2008

Clinical Cancer Research

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Purpose: Neutral endopeptidase (CD10), an ectopeptidase bound to the cell surface, is thought to be a potential prognostic marker for prostate cancer. Experimental Design: Prostate cancer patients (N = 3,261) treated by radical prostatectomy at a single institution were evaluated by using tissue microarray. Follow-up data were available for 2,385 patients. The cellular domain (membranous, membranous-cytoplasmatic, and cytoplasmatic only) of CD10 expression was analyzed immunohistochemically and correlated with various clinical and histopathologic features of the tumors. Results: CD10 expression was detected in 62.2% of cancer samples and occurred preferentially in higher Gleason pattern (P < 0.0001). CD10 expression positively correlated with adverse tumor features such as elevated preoperative prostate-specific antigen (PSA), higher Gleason score, and advanced stage (P < 0.0001 each). Survival analyses showed that PSA recurrence was significantly associated with the staining pattern of CD10 expression. Outcome significantly declined from negative over membranous, membranous-cytoplasmatic, to exclusively cytoplasmatic CD10 expression (P < 0.0001). In multivariate analysis, CD10 expression was an independent predictor for PSA failure (P = 0.0343). Conclusions: CD10 expression is an unfavorable independent risk factor in prostate cancer. The subcellular location of CD10 protein is associated with specific clinical courses, suggesting an effect on different important biological properties of prostate cancer cells. The frequent expression of CD10 in prostate cancer and the strong association of CD10 with unfavorable tumor features may qualify this biomarker for targeted therapies.Neutral endopeptidase (CD10) may be a prognostic molecular marker in prostate cancer. This enzyme is a zinc-dependent, cell surface metallopeptidase that is widely expressed in the epithelial cells of the kidney, breast, lung, intestine, and prostate gland (1). It contains a large extracellular domain that inactivates various physiologically active peptides (e.g., bombesin, substance-P, endothelin-1) by cleavage (1). The exact physiologic significance of CD10 is unknown. CD10 plays a part in different cancers, including prostate cancer, where it has been shown to be involved in the migration, survival, and apoptosis of cancer cells, as well as tumor progression (2). Studies investigating the prognostic significance of the expression of CD10 in prostate cancer generated conflicting results. Zellweger et al. (3) and Freedland et al. (4) did not detect an association between CD10 expression and the recurrence of prostate-specific antigen (PSA) in prostate cancer. Osman et al. (5) reported a poor outcome for patients with CD10 loss; CD10 expression was an unfavorable risk factor in the series of Dall'Era et al. (6).We used an existing large-scale prostate cancer tissue microarray (7) constructed from 3,261 homogenously treated prostate cancers comprising 2,385 patients with follow-up information to further evaluate the potential progno...

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Section: Discussionmentioning

confidence: 99%

Distinct Subcellular Expression Patterns of Neutral Endopeptidase (CD10) in Prostate Cancer Predict Diverging Clinical Courses in Surgically Treated Patients

Fleischmann

Schlomm²,

Huland

et al. 2008

Clinical Cancer Research

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“…A number of studies demonstrate that use of phosphoramidon or inhibition of ECE can reduce elevated blood pressure in genetic and experimental rodent hypertension [1,2,22,27,28,34].…”

Section: Et-1 and Ecementioning

confidence: 99%

Big ET-1 processing into vasoactive peptides in arteries and veins

Watts

Thakali

Smark

et al. 2007

Vascular Pharmacology

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The endothelin (ET) peptides are more potent in contracting veins than arteries. The precursor big ET-1 is metabolized by endothelin converting enzyme [ECE; to ET-1 (1-21)], matrix metalloproteases [MMPs; to ET-1 (1-32)] and chymase [to ET-1(1-31)]. We hypothesized that arteries and veins were differently dependent in conversion of big ET-1 to vasoconstrictors. Immunohistochemical, western, zymographic and isometric contractile assays in rat aorta and vena cava were used. Big ET-1 contracted aorta [60±17% phenylephrine contraction] but was more efficacious in vena cava [478±61% norepinephrine contraction]. ECE and its product ET-1(1-21) were detected in aorta and vena cava, and the ECE inhibitors phosphoramidon and CGS-26393 reduced big ET-1-induced contraction. ET-1 (1-32) contracted aorta and vena cava but inhibition of MMPs with minocycline or GM6001 did not reduce big ET-1 -induced contraction; zymography confirmed active tissue MMPs. Aorta and vena cava contracted to the product of chymase, ET-1 (1-31). Chymase was detected in aorta and only weakly in vena cava. Inhibition of chymase (chymostatin, 100 μM) reduced arterial (19% control) but not venous constriction to big ET-1. These results suggest at least one potential significant difference-the role of chymase--in in vitro enzymatic processing of big ET-1 in arteries and veins.

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“…(Trapani et al, 2004, Battistini, Daull & Jeng., 2005 However, what has been so far advanced allows us to have useful drugs with proven scientific evidence on cardiovascular risk reduction and augur a promising future in reducing cardiovascular morbility and mortality.…”

Section: Discussionmentioning

confidence: 99%

New Therapeutics in Hypertension

Álvarez¹

2012

Antihypertensive Drugs

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CGS 35601, a Triple Inhibitor of Angiotensin Converting Enzyme, Neutral Endopeptidase and Endothelin Converting Enzyme

Cited by 34 publications

References 45 publications

Distinct Subcellular Expression Patterns of Neutral Endopeptidase (CD10) in Prostate Cancer Predict Diverging Clinical Courses in Surgically Treated Patients

Distinct Subcellular Expression Patterns of Neutral Endopeptidase (CD10) in Prostate Cancer Predict Diverging Clinical Courses in Surgically Treated Patients

Big ET-1 processing into vasoactive peptides in arteries and veins

New Therapeutics in Hypertension

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