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Current Drug Delivery Jan 2011The three mammalian bombesin (Bn) receptors (gastrin-releasing peptide [GRP] receptor, neuromedin B [NMB] receptor, BRS-3) are one of the classes of G protein-coupled... (Review)
Review
The three mammalian bombesin (Bn) receptors (gastrin-releasing peptide [GRP] receptor, neuromedin B [NMB] receptor, BRS-3) are one of the classes of G protein-coupled receptors that are most frequently over-express/ectopically expressed by common, important malignancies. Because of the clinical success of somatostatin receptor-mediated imaging and cytotoxicity with neuroendocrine tumors, there is now increasing interest in pursuing a similar approach with Bn receptors. In the last few years then have been more than 200 studies in this area. In the present paper, the in vitro and in vivo results, as well as results of human studies from many of these studies are reviewed and the current state of Bn receptor-mediated imaging or cytotoxicity is discussed. Both Bn receptor-mediated imaging studies as well as Bn receptor-mediated tumoral cytotoxic studies using radioactive and non-radioactive Bn-based ligands are covered.
Topics: Animals; Bombesin; Humans; Ligands; Molecular Targeted Therapy; Neoplasms; Radionuclide Imaging; Receptors, Bombesin
PubMed: 21034419
DOI: 10.2174/156720111793663624 -
International Journal of Molecular... Apr 2023Angiogenesis-related cell-surface molecules, including integrins, aminopeptidase N, vascular endothelial growth factor, and gastrin-releasing peptide receptor (GRPR),... (Review)
Review
Angiogenesis-related cell-surface molecules, including integrins, aminopeptidase N, vascular endothelial growth factor, and gastrin-releasing peptide receptor (GRPR), play a crucial role in tumour formation. Radiolabelled imaging probes targeting angiogenic biomarkers serve as valuable vectors in tumour identification. Nowadays, there is a growing interest in novel radionuclides other than gallium-68 (Ga) or copper-64 (Cu) to establish selective radiotracers for the imaging of tumour-associated neo-angiogenesis. Given its ideal decay characteristics (E: 632 KeV) and a half-life (T = 3.97 h) that is well matched to the pharmacokinetic profile of small molecules targeting angiogenesis, scandium-44 (Sc) has gained meaningful attention as a promising radiometal for positron emission tomography (PET) imaging. More recently, intensive research has been centered around the investigation of Sc-labelled angiogenesis-directed radiopharmaceuticals. Previous studies dealt with the evaluation of Sc-appended ab integrin-affine Arg-Gly-Asp (RGD) tripeptides, GRPR-selective aminobenzoyl-bombesin analogue (AMBA), and hypoxia-associated nitroimidazole derivatives in the identification of various cancers using experimental tumour models. Given the tumour-related hypoxia- and angiogenesis-targeting capability of these PET probes, Sc seems to be a strong competitor of the currently used positron emitters in radiotracer development. In this review, we summarize the preliminary preclinical achievements with Sc-labelled angiogenesis-specific molecular probes.
Topics: Humans; Feasibility Studies; Vascular Endothelial Growth Factor A; Radioisotopes; Bombesin; Receptors, Bombesin; Positron-Emission Tomography; Gallium Radioisotopes; Neovascularization, Pathologic
PubMed: 37108559
DOI: 10.3390/ijms24087400 -
FASEB Journal : Official Publication of... Jun 2018Bombesin receptor subtype 3 (BRS-3) is a GPCR that is expressed in the CNS, peripheral tissues, and tumors. Our understanding of BRS-3's role in physiology and...
Bombesin receptor subtype 3 (BRS-3) is a GPCR that is expressed in the CNS, peripheral tissues, and tumors. Our understanding of BRS-3's role in physiology and pathophysiology is limited because its natural ligand is unknown. In an attempt to identify this ligand, we screened toad skin ( Bufo bufo gargarizans Cantor) extracts and identified prostaglandins as putative ligands. In BRS-3-transfected human embryonic kidney (HEK) cells, we found that prostaglandins, with prostaglandin E2 (PGE2) being the most potent, fulfill the pharmacologic criteria of affinity, selectivity, and specificity to be considered as agonists to the BRS-3 receptor. However, PGE2 is unable to activate BRS-3 in different cellular environments. We speculated that EP receptors might be the cause of this cellular selectivity, and we found that EP is the receptor primarily responsible for the differential PGE2 effect. Consequently, we reconstituted the HEK environment in Chinese hamster ovary (CHO) cells and found that BRS-3 and EP interact to potentiate PGE2 signaling. This potentiating effect is receptor specific, and it occurs only when BRS-3 is paired to EP. Our study represents an example of functional crosstalk between two distantly related GPCRs and may be of clinical importance for BRS-3-targeted therapies.-Zhang, Y., Liu, Y., Wu, L., Fan, C., Wang, Z., Zhang, X., Alachkar, A., Liang, X., Civelli, O. Receptor-specific crosstalk between prostanoid E receptor 3 and bombesin receptor subtype 3.
Topics: Animals; CHO Cells; Cricetulus; Dinoprostone; HEK293 Cells; Humans; Receptors, Bombesin; Receptors, Prostaglandin E, EP3 Subtype; Signal Transduction
PubMed: 29401613
DOI: 10.1096/fj.201700337RR -
Molecular Imaging and Biology Aug 2018Gastrin-releasing peptide receptors (GRPRs), part of the bombesin (BBN) family, are aberrantly overexpressed in many cancers, including those of the breast, prostate,... (Review)
Review
Gastrin-releasing peptide receptors (GRPRs), part of the bombesin (BBN) family, are aberrantly overexpressed in many cancers, including those of the breast, prostate, pancreas, and lung, and therefore present an attractive target for cancer diagnosis and therapy. Different bombesin analogs have been radiolabeled and used for imaging diagnosis, staging, evaluation of biochemical recurrence, and assessment of metastatic disease in patients with prostate cancer. Recently, interest has shifted from BBN-like receptor agonists to antagonists, because the latter does not induce adverse effects and demonstrate superior in vivo pharmacokinetics. We review the preclinical and clinical literatures on the use of GRPRs as targets for imaging and therapy of prostate cancer, with a focus on the newer developments and theranostic potential of GRPR peptides.
Topics: Animals; Bombesin; Humans; Male; Neoplasm Staging; Prostatic Neoplasms; Receptors, Bombesin; Theranostic Nanomedicine
PubMed: 29256046
DOI: 10.1007/s11307-017-1151-1 -
Biochemical Pharmacology Sep 2016Bombesin-receptor-subtype-3 (BB3 receptor) is a G-protein-coupled-orphan-receptor classified in the mammalian Bombesin-family because of high homology to...
Bombesin-receptor-subtype-3 (BB3 receptor) is a G-protein-coupled-orphan-receptor classified in the mammalian Bombesin-family because of high homology to gastrin-releasing peptide (BB2 receptor)/neuromedin-B receptors (BB1 receptor). There is increased interest in BB3 receptor because studies primarily from knockout-mice suggest it plays roles in energy/glucose metabolism, insulin-secretion, as well as motility and tumor-growth. Investigations into its roles in physiological/pathophysiological processes are limited because of lack of selective ligands. Recently, a selective, peptide-antagonist, Bantag-1, was described. However, because BB3 receptor has low-affinity for all natural, Bn-related peptides, little is known of the molecular basis of its high-affinity/selectivity. This was systematically investigated in this study for Bantag-1 using a chimeric-approach making both Bantag-1 loss-/gain-of-affinity-chimeras, by exchanging extracellular (EC) domains of BB3/BB2 receptor, and using site-directed-mutagenesis. Receptors were transiently expressed and affinities determined by binding studies. Bantag-1 had >5000-fold selectivity for BB3 receptor over BB2/BB1 receptors and substitution of the first EC-domain (EC1) in loss-/gain-of affinity-chimeras greatly affected affinity. Mutagenesis of each amino acid difference in EC1 between BB3 receptor/BB2 receptor showed replacement of His(107) in BB3 receptor by Lys(107) (H107K-BB3 receptor-mutant) from BB2 receptor, decreased affinity 60-fold, and three replacements [H107K, E11D, G112R] decreased affinity 500-fold. Mutagenesis in EC1's surrounding transmembrane-regions (TMs) demonstrated TM2 differences were not important, but R127Q in TM3 alone decreased affinity 400-fold. Additional mutants in EC1/TM3 explored the molecular basis for these changes demonstrated in EC1, particularly important is the presence of aromatic-interactions by His(107), rather than hydrogen-bonding or charge-charge interactions, for determining Bantag-1 high affinity/selectivity. In regard to Arg(127) in TM3, both hydrogen-bonding and charge-charge interactions contribute to the high-affinity/selectivity for Bantag-1.
Topics: Animals; CHO Cells; Cricetulus; Humans; Mice; Mutagenesis; Peptides; Protein Binding; Receptors, Bombesin; Recombinant Fusion Proteins
PubMed: 27346274
DOI: 10.1016/j.bcp.2016.06.013 -
The International Journal of... 2005Amphibian bombesin and its related peptides consist a family of neuropeptides in many vertebrate species. Bombesin and two major bombesin-like peptide in mammals,... (Review)
Review
Amphibian bombesin and its related peptides consist a family of neuropeptides in many vertebrate species. Bombesin and two major bombesin-like peptide in mammals, gastrin-releasing peptide (GRP) and neuromedin B (NMB), have been shown to elicit various physiological effects. These include inhibition of feeding, smooth muscle contraction, exocrine and endocrine secretions, thermoregulation, blood pressure and sucrose regulations and cell growth. Receptors for GRP and NMB (GRP-R and NMB-R), as well as third subtype of bombesin-like peptide receptor (BRS-3) have been cloned. These receptors are G-protein-coupled receptors and are expressed in various brain regions and in the digestive tract. In this paper, we will summarize studies on these peptides and their receptors, with special reference to research using gene-knockout mice. These studies clearly demonstrated the role of three receptors in vivo and in vitro. We will also discuss the phylogeny of these receptors.
Topics: Amino Acid Sequence; Amphibians; Animals; Bombesin; Brain Chemistry; Chickens; Cloning, Molecular; Conserved Sequence; Humans; Mice; Molecular Sequence Data; Rats; Receptors, Bombesin; Sequence Alignment; Sequence Homology, Amino Acid
PubMed: 15906244
DOI: 10.1387/ijdb.041954ho -
Journal of Nuclear Medicine : Official... Oct 2016Imaging plays an important role in prostate cancer (PC), including accurate evaluation of the extent of disease, assessment of sites of recurrent disease, and monitoring... (Review)
Review
Imaging plays an important role in prostate cancer (PC), including accurate evaluation of the extent of disease, assessment of sites of recurrent disease, and monitoring of response to treatment. Molecular imaging techniques are among the novel developments related to the imaging of PC, and various SPECT and PET radiopharmaceuticals are now available in clinical trials or commercially. Here we describe the preclinical and clinical use of gastrin-releasing peptide receptors as targets for the imaging of PC, with a focus on the development of PET tracers for the imaging of gastrin-releasing peptide receptor-positive tumors.
Topics: Biomarkers, Tumor; Bombesin; Evidence-Based Medicine; Humans; Image Enhancement; Male; Molecular Imaging; Positron-Emission Tomography; Prostatic Neoplasms; Radiopharmaceuticals; Receptors, Bombesin
PubMed: 27694175
DOI: 10.2967/jnumed.115.170977 -
Nature Communications Jun 2020Itch, in particular chronic forms, has been widely recognized as an important clinical problem, but much less is known about the mechanisms of itch in comparison with... (Review)
Review
Itch, in particular chronic forms, has been widely recognized as an important clinical problem, but much less is known about the mechanisms of itch in comparison with other sensory modalities such as pain. Recently, considerable progress has been made in dissecting the circuit mechanisms of itch at both the spinal and supraspinal levels. Major components of the spinal neural circuit underlying both chemical and mechanical itch have now been identified, along with the circuits relaying ascending transmission and the descending modulation of itch. In this review, we summarize the progress in elucidating the neural circuit mechanism of itch at spinal and supraspinal levels.
Topics: Animals; Brain; Gastrin-Releasing Peptide; Humans; Neurons; Pruritus; Receptors, Bombesin; Signal Transduction; Spinal Cord
PubMed: 32546780
DOI: 10.1038/s41467-020-16859-5 -
Pharmaceutics Nov 2023Recently, bombesin (BN) and its analogs have attracted much attention as excellent anticancer agents because they interact with specific receptors widely distributed on... (Review)
Review
Recently, bombesin (BN) and its analogs have attracted much attention as excellent anticancer agents because they interact with specific receptors widely distributed on the surface of various cancer cells. However, their biological properties proceed far beyond this, given a broad spectrum of activity. Bombesin receptor ligands are effective drugs for the treatment of rheumatoid arthritis or gastrointestinal diseases. However, most diseases are complex, and the use of polytherapy may lead to pharmacokinetic and pharmacodynamic drug-drug interactions, resulting in side effects. Therefore, there is a need to develop effective compounds that also contain BN or its analogs, which are combined with other structural entities, thus generating a so-called hybrid drug. Hybrid drugs that contain bombesin pharmacophore(s) may be proposed as a solution to the problem of polytherapy or the lack of an effective cure. Such structures have now demonstrated the desired efficacy, though information on these aforementioned compounds is relatively scarce. Therefore, our paper aims to encourage researchers to focus on bombesins. Herein, we indicate that the hybrid approach should also be firmly applied to bombesins and the BN receptor family. This paper's structure is divided into two main sections demonstrating bombesins and their properties, as well as recent data on bombesin-based hybrid compounds and their potential usefulness in medicine. Overall, it refers to the discovery and synthesis of modified bombesin-based hybrid compounds.
PubMed: 38004575
DOI: 10.3390/pharmaceutics15112597 -
International Journal of Molecular... Feb 2023Advances in nanomedicine bring the attention of researchers to the molecular targets that can play a major role in the development of novel therapeutic and diagnostic... (Review)
Review
Advances in nanomedicine bring the attention of researchers to the molecular targets that can play a major role in the development of novel therapeutic and diagnostic modalities for cancer management. The choice of a proper molecular target can decide the efficacy of the treatment and endorse the personalized medicine approach. Gastrin-releasing peptide receptor (GRPR) is a G-protein-coupled membrane receptor, well known to be overexpressed in numerous malignancies including pancreatic, prostate, breast, lung, colon, cervical, and gastrointestinal cancers. Therefore, many research groups express a deep interest in targeting GRPR with their nanoformulations. A broad spectrum of the GRPR ligands has been described in the literature, which allows tuning of the properties of the final formulation, particularly in the field of the ligand affinity to the receptor and internalization possibilities. Hereby, the recent advances in the field of applications of various nanoplatforms that are able to reach the GRPR-expressing cells are reviewed.
Topics: Humans; Bombesin; Nanomedicine; Neoplasms; Receptors, Bombesin; Theranostic Nanomedicine
PubMed: 36834867
DOI: 10.3390/ijms24043455