Current Drug Targets - Volume 17, Issue 5, 2016

Receptors for LHRH (luteinizing hormone-releasing hormone) are expressed in about 80% of human endometrial, ovarian and prostate cancers and are also found in more than 50% of breast cancers including triple negative breast cancers. In the human body, LHRH receptors are found at significant levels in the pituitary and reproductive organs. Other benign tissues or hematopoietic stem cells express only low levels of receptors for LHRH or no receptors. Thus LHRH receptors are promising targets for a receptor- mediated chemotherapy with cytotoxic hybrid molecules. Cytotoxic analogs of LHRH consist of a LHRH agonist, which is used as a carrier peptide and DOX or its derivatives. Cytotoxic analogs of LHRH, AEZS-108 (formerly known as AN-152) and AN-207, exhibit anti-cancer activity in various in vitro and in vivo models of LHRH-receptor positive cancers. In AEZS-108 (zoptarelin DOX) DOX is covalently linked to the LHRH agonist [D-Lys6]LHRH. Results of phase I and II clinical studies in patients with breast, endometrial and ovarian cancers demonstrated good anticancer activity with moderate toxic side effects and without any sign of cardiotoxicity so far. AEZS-108 is also being evaluated in phase I/II studies in castration resistant prostate cancer and metastatic bladder cancer. Because of the very promising phase II results in endometrial cancer, a multinational, multicenter phase III study of this malignancy has been initiated and is currently recruiting patients.

Ghrelin is orexigenic hormone primarily synthesized by endocrine X/A-like cells of gastric oxyntic mucosa to stimulate appetite and food intake along with regulation of growth hormone and insulin secretion; glucose and lipid metabolism; gastrointestinal motility; blood pressure, heart rate and neurogenesis. Furthermore, peripherally (after crossing the blood brain barrier) as well as centrally synthesized ghrelin (in the hypothalamus) regulates diverse functions of central nervous system including stress-associated behavioral functions. Exposure to stress alters the ghrelin levels and alteration in ghrelin levels significantly affects neuro-endocrinological parameters; metabolism-related physiology, behavior and mood. Studies have shown both anxiolytic and anxiogenic role of ghrelin suggesting its dual role in modulating anxiety-related behavior. However, it is proposed that increase in ghrelin levels during stress condition is an endogenous stress coping behavior and increased ghrelin levels may be required to prevent excessive anxiety. In preclinical and clinical studies, an elevation in ghrelin levels during depression has been correlated with their antidepressant activities. Ghrelin-induced modulation of stress and associated conditions has been linked to alteration in hypothalamic- pituitary-adrenal (HPA) axis; autonomic nervous system (mainly sympathetic nervous system and serotonergic neurotransmission. A reciprocal relationship has been reported between corticotropin-releasing hormone (CRH) and ghrelin as ghrelin increases the release of CRH, ACTH and corticosteroids; while CRH decreases the expression of ghrelin. Similarly, ghrelin increases the serotonin turnover and in turn, serotonin controls ghrelin signaling to modulate anxietyrelated behavior. The present review discusses the dual role of ghrelin in stress and related behavioral disorders along with possible mechanisms.

Growth factors of the bombesin/gastrin releasing peptide (BN/GRP) family play a critical role in proliferation and progression of malignancies. Inhibitors targeting GRP signalling have been developed and tested as anticancer compounds showing promising preclinical and early phase clinical results. In this review, we will discuss the molecular signaling, expression and the functional role of BN/GRP-GRPR in different cancer models and will focus on the available strategies to target BN/GRP-GRPR in cancer treatment as well as in tumour diagnosis and follow up.

Many studies have suggested that CXCR3, CXCR5, CXCR6 and CXCR7 chemokine receptors are determinant in type 1 diabetes (T1D), expecially in autoimmunity and β-cell destruction. In particular circulating CXCL10 level (the ligand of CXCR3) is high in T1D patients, and this suggests that CXCL10 may be a candidate for a predictive marker of T1D. Blocking the CXCL10/CXCR3 axis in newly onset of diabetes seems to be a potential strategy for the therapy of T1D. Attempts have been done in modulating or blocking CXCR5, CXCR6 and CXCR7 chemokine receptors in experimental settings of T1D. More researches are necessary to evaluate the interplay among cytokines, chemokines and the pathogenesis and therapy of T1D.

Lung cancer kills approximately 1.3 million citizens in the world annually. The tyrosine kinase inhibitors (TKI) erlotinib and gefitinib are effective anti-tumor agents especially in lung cancer patients with epidermal growth factor receptor (EGFR) mutations. The goal is to increase the potency of TKI in lung cancer patients with wild type EGFR. G protein-coupled receptors (GPCR) transactivate the wild type EGFR in lung cancer cells. The GPCR can be activated by peptide agonists causing phosphatidylinositol turnover or stimulation of adenylylcyclase. Recently, nonpeptide antagonists were found to inhibit the EGFR transactivation caused by peptides. Nonpeptide antagonists for bombesin (BB), neurotensin (NTS) and cholecystokinin (CCK) inhibit lung cancer growth and increase the cytotoxicity of gefitinib. The results suggest that GPCR transactivation of the EGFR may play an important role in cancer cell proliferation.

Somatostatin (SST) is a cyclic hormone-release inhibitory peptide that has high binding affinity to all of its five SST receptors (SSTRs). SST negatively regulates cell proliferation and the release of multiple hormones via activation of its cognate receptors. A variety of SST analogs, some with high affinity and selectivity of receptor subtypes, have been synthesized and developed. Certain longacting SST analogs such as octreotide, lanreotide and pasireotide have been clinically applied to the treatment of human diseases such as those caused by excessive release of growth hormone (acromegaly), or adrenocorticotropic hormone (Cushing’s syndrome), and for the treatment of carcinoid syndrome. Investigations into new biological activities of these long-acting SSTs and their possible clinical applications are also still ongoing. Also, novel SST analogs are being designed and developed to target different receptor subtype(s) or mimic natural SST’s multiple biological properties. Additionally, since SSTRs, especially SSTR2, are aberrantly expressed in many cancer cells and tumor blood vessels, internalizing SST analogs is currently being used as drug-delivery vehicle for the application of receptor-targeted therapeutics. This review will discuss recent advances in the development and applications of SST and its analogs

Extensive research over the past thirty years has demonstrated a vital role for metabotropic glutamate (mGlu) receptors in the major functions of the central nervous system (CNS). A wealth of preclinical studies provide evidence that pharmacological targeting of mGlu receptors can effectively attenuate the development of symptoms and progression of many CNS disorders in animal models. In this review we summarize the current knowledge on the involvement of mGlu receptors in the pathophysiology of neuropsychiatric disorders (schizophrenia, depression, anxiety and cognitive disorders, pain perception and addiction), as well as neurodegenerative (Alzheimer’s, Huntington’s and Parkinson’s diseases) and neurodevelopmental (fragile X syndrome and autism spectrum disorders) diseases. We further emphasize the therapeutic potential of mGlu receptors’ pharmacological modulators in these diseases, describe the results of clinical trials with these compounds and discuss the potential sources of translational difficulties.