SR48692 is a neurotensin receptor antagonist which inhibits the growth of small cell lung cancer cells

Moody, Terry W.; Chiles, Jessica; Casibang, Marchessini; Moody, Elizabeth; Chan, Daniel C.; Davis, Thomas P.

doi:10.1016/s0196-9781(00)00362-4

Cited by 51 publications

(34 citation statements)

References 32 publications

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“…Nevertheless, neurotensin was found to be released from gut and pancreas cancers and has been identified as a gene associated with enhanced metastasis in a lung carcinoma cell line (40,45). Additionally, it has been shown that the NT1 receptor antagonist SR48692 inhibited the growth of human colon and lung cancer cells xenografted in mice (46). In this report, we further establish the contribution of endogenous or tumoral neurotensin within the breast cancer progression by showing the reversibility of its tumorigenic effects through silencing RNA and direct pharmacologic blockades.…”

Section: Discussionmentioning

confidence: 54%

Expression of Neurotensin and NT1 Receptor in Human Breast Cancer: A Potential Role in Tumor Progression

et al. 2006

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Emerging evidence supports neurotensin as a trophic and antiapoptotic factor, mediating its control via the highaffinity neurotensin receptor (NT1 receptor) in several human solid tumors. In a series of 51 patients with invasive ductal breast cancers, 34% of all tumors were positive for neurotensin and 91% positive for NT1 receptor. We found a coexpression of neurotensin and NT1 receptor in a large proportion (30%) of ductal breast tumors, suggesting a contribution of the neurotensinergic signaling cascade within breast cancer progression. Functionally expressed NT1 receptor, in the highly malignant MDA-MB-231 human breast cancer cell line, coordinated a series of transforming functions, including cellular migration, invasion, induction of the matrix metalloproteinase (MMP)-9 transcripts, and MMP-9 gelatinase activity. Disruption of NT1 receptor signaling by silencing RNA or use of a specific NT1 receptor antagonist, SR48692, caused the reversion of these transforming functions and tumor growth of MDA-MB-231 cells xenografted in nude mice. Our findings support the contribution of neurotensin in human breast cancer progression and point out the utility to develop therapeutic molecules targeting neurotensin or NT1 receptor signaling cascade. These strategies would increase the range of therapeutic approaches and be beneficial for specific patients. (Cancer Res 2006; 66(12): 6243-9)

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Section: Discussionmentioning

confidence: 54%

Expression of Neurotensin and NT1 Receptor in Human Breast Cancer: A Potential Role in Tumor Progression

et al. 2006

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“…It is worth noting that a number of other peptidic antagonists have been found to interfere with cell proliferation in a complex and only partially understood manner, including the bradykinin B2 antagonist Hoe140 (33), the "dipeptoid" CCK-B/ gastrin agents (34), the neurotensin receptor antagonist SR48692 (35), the leukotriene B4 receptor antagonist LY293111 (36), and the somatostatin receptor antagonist cSSTA (37). It will be interesting to verify whether the complex effects on cell growth by these peptides may also be explained by a biased agonist action on their receptors.…”

Section: Discussionmentioning

confidence: 99%

“…Drug analogues capable of promoting a selective receptor-G protein coupling may be of great pharmacological and clinical importance because they may target only one specific signal transduction pathway. Here, we report that atosiban, an oxytocin derivative that acts as a competitive antagonist on OTR/G q coupling, displays agonistic properties on OTR/G i coupling, as shown by specific 35 …”

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confidence: 95%

The Oxytocin Receptor Antagonist Atosiban Inhibits Cell Growth via a “Biased Agonist” Mechanism

Reversi

Rimoldi

Marrocco

et al. 2005

Journal of Biological Chemistry

114

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In human myometrial cells, the promiscuous coupling of the oxytocin receptors (OTRs) to G q and G i leads to contraction. However, the activation of OTRs coupled to different G protein pathways can also trigger opposite cellular responses, e.g. OTR coupling to G i inhibits, whereas its coupling to G q stimulates, cell proliferation. WAF1/CIP1 induction, the same signaling events leading to oxytocin-mediated cell growth inhibition via a G i pathway. Finally, atosiban exposure did not cause OTR internalization and led to only a modest decrease (20%) in the number of high affinity cell membrane OTRs, two observations consistent with the finding that atosiban did not lead to any desensitization of the oxytocin-induced activation of the G q -phospholipase C pathway. Taken together, these observations indicate that atosiban acts as a "biased agonist" of the human OTRs and thus belongs to the class of compounds capable of selectively discriminating only one among the multiple possible active conformations of a single G protein-coupled receptor, thereby leading to the selective activation of a unique intracellular signal cascade.

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“…(11)(12)(13). The disruption of the neurotensinergic pathway through a specific antagonist, in experimental tumors from colon, breast, and small cell lung cancer cells, caused a strong reduction in tumor growth (14)(15)(16). We had previously shown the presence of a chronic self-activation loop between neurotensin and NTSR1, as one mechanism responsible for the constitutive activation of the mitogen-activated protein kinase mitogenic signaling pathways along with sustained target gene activation (17)(18)(19)(20).…”

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confidence: 99%

Neurotensin Receptor 1 Determines the Outcome of Non–Small Cell Lung Cancer

Alifano

Souazé

Dupouy

et al. 2010

Clinical Cancer Research

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Purpose: This study aimed to investigate the role of the neurotensin/neurotensin receptor I (NTSR1) complex in non-small cell lung cancer (NSCLC) progression.Experimental Design: The expression of neurotensin and NTSR1 was studied by transcriptome analysis and immunohistochemistry in two series of 74 and 139 consecutive patients with pathologic stage I NSCLC adenocarcinoma. The findings were correlated with clinic-pathologic features. Experimental tumors were generated from the malignant human lung carcinoma cell line A459, and a subclone of LNM35, LNM-R. The role of the neurotensin signaling system on tumor growth and metastasis was investigated by small hairpin RNA-mediated silencing of NTSR1 and neurotensin.Results: Transcriptome analysis carried out in a series of 74 patients showed that the positive regulation of NTSR1 put it within the top 50 genes related with relapse-free survival. Immunohistochemistry revealed neurotensin-and NTSR1-positive staining in 60.4% and 59.7% of lung adenocarcinomas, respectively. At univariate analysis, NTSR1 expression was strongly associated with worse 5-year overall survival rate (P = 0.0081) and relapse-free survival (P = 0.0024). Multivariate analysis showed that patients over 65 years of age (P = 0.0018) and NTSR1 expression (P = 0.0034) were independent negative prognostic factors. Experimental tumor xenografts generated by neurotensin-and NTSR1-silenced human lung cancer cells revealed that neurotensin enhanced primary tumor growth and production of massive nodal metastasis via autocrine and paracrine regulation loops.Conclusion: NTSR1 expression was identified as a potential new prognostic biomarker for surgically resected stage I lung adenocarcinomas, as NTSR1 activation was shown to participate in lung cancer progression.

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SR48692 is a neurotensin receptor antagonist which inhibits the growth of small cell lung cancer cells

Cited by 51 publications

References 32 publications

Expression of Neurotensin and NT1 Receptor in Human Breast Cancer: A Potential Role in Tumor Progression

Expression of Neurotensin and NT1 Receptor in Human Breast Cancer: A Potential Role in Tumor Progression

The Oxytocin Receptor Antagonist Atosiban Inhibits Cell Growth via a “Biased Agonist” Mechanism

Neurotensin Receptor 1 Determines the Outcome of Non–Small Cell Lung Cancer

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