Current Pharmaceutical Design - Volume 22, Issue 16, 2016

Inositol polyphosphate 5-phosphatases act on inositol phosphates and phosphoinositides as substrates. They are 10 different isoenzymes and several splice variants in the human genome that are involved in a series of human pathologies such as the Lowe syndrome, the Joubert and MORM syndromes, breast cancer, glioblastoma, gastric cancer and several other type of cancers. Inositol 5-phosphatases can be amplified in human cancer cells, whereas the 3- and 4- phosphatase tumor suppressor PTEN and INPP4B, repectively are often repressed or deleted. The inositol 5-phosphatases are critically involved in a complex network of higly regulated phosphoinositides, affecting the lipid content of PI(3, 4, 5)P3, PI(4, 5)P2 and PI(3, 4)P2. This has an impact on the normal behavior of many intracellular target proteins e.g. protein kinase B (PKB/Akt) or actin binding proteins and final biological responses. The production of PI(3, 4P)2 by dephosphorylation of the substrate PI(3, 4, 5)P3 is particularly important as it produces a new signal messenger in the control of cell migration, invasion and endocytosis. New inhibitors/activators of inositol 5- phosphatases have recently been identified for the possible control of their activity in several human pathologies such as inflamation and cancer.

The development of targeted therapy drugs acting on tumor growth and progression is greatly expanding these last years. Among them kinase inhibitors have a prominent position and have demonstrated efficacy and clinical benefits in solid and hematologic malignancies. Compared to conventional systemic cytotoxic chemotherapeutic agents, their specific mechanism of action limits the occurrence of adverse events. However, as targeted kinases are shared by normal cells, their inhibition can affect physiological cell function. In this review we will focus on the side effects of kinase inhibitors on blood platelets which actively use kinase-related signalling pathways to prevent haemorrhages following vessel injury. Major functions of platelets are to adhere to the subendothelial matrix and to aggregate to form a haemostatic plug preventing excessive blood loss upon vascular lesion. Several kinase inhibitors including dasatinib and ibrutinib have been reported to affect specific steps of platelet activation process and to increase bleeding risk. This has important clinical implications particularly in patients treated with antithrombotic drugs. We will describe the effect of kinase inhibitors known to affect platelet activation and discuss the potential impact of those under development that may also interfere with platelet functions.

Hematopoietic and mesenchymal stem and progenitor cells are organized in the osteo-hematopoietic niche, a complex microenvironment ensuring self-renewal and differentiation. Perturbations of the niche architecture, the mutual cellular interactions and signaling pathways disrupt tissue homeostasis resulting in cytopenia and malignant diseases such as myelodysplastic syndromes (MDS), supporting the concept of niche-induced oncogenesis. Analyzing the available treatment options for patients harboring MDS, it becomes evident that many of them specifically modify components of the stem cell niche. Hereby especially compounds inhibiting the TGF-β superfamily seem to represent a promising novel approach for patients with anemia as a result of ineffective erythropoiesis. Moreover, apart from affecting tumorigenesis, these drugs appear to influence bone structure and function as well as hematopoiesis in elderly MDS patients with a disturbed microarchitecture of the bone marrow. In the present review we will dissect the contribution of components of the stem cell niche for the pathogenesis of MDS and discuss current therapeutic strategies targeting components of the niche, focusing on the modulation of TGF-β signaling.

Splicing is an essential cellular process which is carried out by the spliceosome in order to remove the introns and join the exons present in pre-mRNA transcripts. A variety of spliceosomal mutations have been recently identified in the myelodysplastic syndromes (MDS), a heterogeneous group of hematopoietic stem cell malignancies, revealing a new leukemogenic pathway involving spliceosomal dysfunction. Splicing factor genes are the most frequently mutated genes found in MDS, with mutations occurring in more than half of all patients. The high mutation frequency in different components of the spliceosome in MDS indicates that aberrant splicing may be a common consequence of these mutations in this disorder. RNA sequencing studies using MDS patient bone marrow cells and different mouse models have identified several downstream targets of the splicing factor mutations. Aberrant splicing of these target genes may contribute to MDS pathogenesis, however functional studies are required in order to fully determine the effects of the aberrant isoforms on disease phenotype. Splicing inhibitors are currently being developed and may be used as therapeutic agents to target aberrant pre-mRNA splicing in MDS and other cancers with splicing factor mutations. The mouse models expressing splicing factor mutations may prove particularly valuable for pre-clinical testing of these drugs.

Nuclear phosphoinositide-phospholipase C (PI-PLC) beta1 plays a crucial role in the molecular steps that regulate cell proliferation and differentiation in several experimental models, such as myoblasts and hematopoietic cells, via interaction with other important molecular players. Indeed, PI-PLCbeta1 and its related molecules are definitely involved in hematopoiesis, and particularly in drug-induced myeloid or erythroid differentiation. Here, we review the role of nuclear PI-PLCbeta1 signalling in normal hematopoiesis, in pathogenesis and in drug-related induction of hematopoietic differentiation, with particular reference to the current therapy of Myelodysplastic Syndromes (MDS).

Myelodysplastic syndromes (MDS) are a heterogeneous group of hematologic diseases, mainly affecting the elderly, characterized by unilinear or multilinear peripheral cytopenia, bone marrow ineffective haemopoiesis, and a varying risk of progression to acute myeloid leukemia (AML). On the basis of the prognostic score systems currently used, MDS patients are generally classified as having higher risk (HR) or lower risk (LR) MDS. Two drugs, azacitidine (AZA) and decitabine (DAC), defined, because of their proven mechanism of action, as DNA methyltransferase inhibitors (DNMTIs), or hypomethylating agents (HMAs), have proven effective in improving peripheral cytopenias and quality of life, reducing or eliminating transfusion need, delaying leukemic evolution, and (only for AZA) prolonging overall survival (OS). HMAs are currently the first therapeutic choice for MDS patients who are not candidates for allogeneic hematopoietic stem cell transplantation (allo-HSCT). HMAs have also been used before and after allo-HSCT, but their role in this setting needs to be confirmed by larger studies. Although data from several clinical and biological studies might help to identify patients with a higher probability to respond to HMAs, to date this treatment should not be denied to any HR MDS patient. Several attempts have been made to combine HMAs with other therapeutic agents, and these results await confirmation by further studies.

The roles of the epidermal growth factor receptor (EGFR) signaling pathway in various cancers including breast, bladder, brain, colorectal, esophageal, gastric, head and neck, hepatocellular, lung, neuroblastoma, ovarian, pancreatic, prostate, renal and other cancers have been keenly investigated since the 1980’s. While the receptors and many downstream signaling molecules have been identified and characterized, there is still much to learn about this pathway and how its deregulation can lead to cancer and how it may be differentially regulated in various cell types. Multiple inhibitors to EGFR family members have been developed and many are in clinical use. Current research often focuses on their roles and other associated pathways in cancer stem cells (CSCs), identifying sites where therapeutic resistance may develop and the mechanisms by which microRNAs (miRs) and other RNAs regulate this pathway. This review will focus on recent advances in these fields with a specific focus on breast cancer and breast CSCs. Relatively novel areas of investigation, such as treatments for other diseases (e.g., diabetes, metabolism, and intestinal parasites), have provided new information about therapeutic resistance and CSCs.

Psychological stress is an emotion experienced when people are under mental pressure or encounter unexpected problems. Extreme or repetitive stress increases the risk of developing human disease, including cardiovascular disease (CVD), immune diseases, mental disorders, and cancer. Several studies have shown an association between psychological stress and cancer growth and metastasis in animal models and case studies of cancer patients. Stress induces the secretion of stress-related mediators, such as catecholamine, cortisol, and oxytocin, via the activation of the hypothalamic-pituitary-adrenocortical (HPA) axis or the sympathetic nervous system (SNS). These stress-related hormones and neurotransmitters adversely affect stress-induced tumor progression and cancer therapy. Catecholamine is the primary factor that influences tumor progression. It can regulate diverse cellular signaling pathways through adrenergic receptors (ADRs), which are expressed by several types of cancer cells. Activated ADRs enhance the proliferation and invasion abilities of cancer cells, alter cell activity in the tumor microenvironment, and regulate the interaction between cancer and its microenvironment to promote tumor progression. Additionally, other stress mediators, such as glucocorticoids and oxytocin, and their cognate receptors are involved in stress-induced cancer growth and metastasis. Here, we will review how each receptor-mediated signal cascade contributes to tumor initiation and progression and discuss how we can use these molecular mechanisms for cancer therapy.

Objectives:-To examine the effect of nicotine (Ni) on bone socket healing treated with Ellagic acid (EA) after tooth extraction in rat. Materials and Methods: Thirty-Two Sprague Dawley (SD) male rats were divided into four groups. The group 1 was administrated with distilled water intragastrically and injected sterile saline subcutaneously. The group 2 was administrated with EA orally and injected with sterile saline subcutaneously. The groups 3 & 4 were subcutaneously exposed to Ni for 4 weeks twice daily before tooth extraction procedure, and maintained Ni injection until the animals were sacrificed. After one month Ni exposure, the group 4 was fed with EA while continuing Ni injection. All the groups were anesthetized, and the upper left incisor was extracted. Four rats from each group were sacrificed on 14th and 28th days. Tumour necrosis factor alpha (TNFα), Interleukin-1 beta (IL-1β) and Interleukin-6 (IL-6) were applied to assess in serum rat at 14th and 28th days. Superoxide dismutase (SOD) and Thiobarbituric acid reactive substances (TBRAS) levels were assessed to evaluate the antioxidant status and lipid peroxidation accordingly after tooth extraction in homogenized gingival maxilla tissue of rat at 14th and 28th days. The socket hard tissue was stained by eosin and hematoxylin (H); immunohistochemical technique was used to assess the healing process by Osteocalcin (OCN) and Alkaline Phosphatase (ALP) biomarkers. Results: Ni-induced rats administered with EA compound (Group 4) dropped the elevated concentration of pro-inflammatory cytokines significantly when compared to Ni-induced rats (Group 3) (p<0.05). Ni-induced rats administrated with EA compound (Group 4) showed significant production of SOD and recession in TBRAS level when compared to Ni-induced rats (Group 3) (p<0.05). The immunohistochemistry analysis has revealed that OCN and ALP have presented stronger expression in Ni-induced rats treated with EA (Group 4), as against Ni-induced rats (Group 3). Conclusion: We have concluded that, Ni-induced rats, treated with EA have exerted positive effect on the trabecular bone formation after tooth extraction in nicotinic rats could be due to the antioxidant activity of EA which lead to upregulate of OCN and ALP proteins which are responsible for osteogenesis.

Despite advances in understanding the pathophysiology of Alzheimer’s disease (AD), its therapy remains largely symptomatic and supportive. Acetylcholinesterase inhibitors - the first-line drugs used today do not prevent and treat AD. So far, over 90 Phase 3 trials of AD have been unsuccessful with 99.0% failure rate. There is, therefore, an urgent need to find effective new therapies for AD. Owing to the multifactorial nature of AD pathogenesis, polypharmacy with drugs that target heterogeneous pathophysiological pathways, needs to be considered. Fortunately, several drugs used currently in clinical use as monotherapies can be exploited in AD. This article, therefore, presents a novel pharmacological treatment paradigm and recommends the use of valuable diseasemodifying approved drugs, viz. melatonin, minocycline, modafinil, and memantine (the “M” Drugs). Melatonin - a neuroprotector is an antioxidant and anti-inflammatory. Minocycline is also neuroprotective, it reduces neuroinflammation and CNS pathology and prevents cell death. Sleep deprivation leads to decreased hippocampal neurogenesis, increased amyloid beta generation, and causes memory dysfunction. Modafinil - a wake-promoting agent is approved for use in narcolepsy and obstructive sleep apnea. It improves global mental status, hippocampal neurogenesis, attention, and cognition. Memantine is an uncompetitive N-methyl-d-aspartic acid receptor antagonist and is approved for the management of moderate-to-severe AD. The paramount possible beneficial effects of the M-drugs may include significant memory and cognitive enhancement in aging, mild cognitive impairment, and AD. The M drugs-centric pharmacotherapy strategy is comprehensive and pragmatic and is meant to combat multiple pathological targets and ameliorate cognitive dysfunction/AD.

Multiple pathogenic mechanisms contribute to the development of colorectal cancer. This tumor is characterized by high chemoresistance and low immunogenicity due to the effective mechanisms of immunosuppression. Dendritic cells (DCs) play a key role in recognition of tumor antigens and induction of T-cell-primed anticancer response. However, in cancer microenvironment, the function of tumor-infiltrating DCs becomes impaired and switched from the immunostimulation to the immunosuppression. Colorectal cancer cells express anti-inflammatory cytokines such as IL-10 and TGF-β that could affect DC phenotype and support tumor escape from the immune surveillance. As a result, tumor-associated DCs display numerous defects in antigen-presenting capacity and have an altered pattern of expression of immune costimulatory molecules towards the immunoregulatory phenotype. Indeed, understanding of mechanisms, such as how tumor could impair activity of DCs, would help in the development of new DC-based vaccines against colorectal cancer.

Gluten intolerance is an umbrella term for gluten-related disorders manifested in health decline as a result of the gluten ingestion. The spectrum of gluten-related disorders includes three major groups: autoimmune (mainly, Celiac Disease, CD, also known as Celiac Sprue, dermatitis herpetiformis, or gluten-sensitive ataxia), allergic (wheat allergy, WA), and non-autoimmune non-allergic (non-celiac gluten sensitivity, NCGS, or gluten sensitivity, GS). Pathogenesis and diagnostics of CD and WA are well established in contrast to NCGS, pathogenicity of which is still poorly understood and its symptoms are frequently misdiagnosed since most of the NCGS cases are currently identified via the process of CD and WA exclusion. By now, the only one proven effective way for CD treatment is gluten-free diet (GFD). However, such an increasingly gaining popularity diet is apparently unsuitable for NCGS treatment because in this case gluten does not always arise as the major or exclusive culprit of gastrointestinal disorder. Furthermore, it is some physicians’ opinion that GFD can be deficient in fiber and in other vitamins and minerals. In many cases, GFD is commercially inaccessible for the most needy, whereas strict adherence to the diet is complicated by the presence of small amounts of the gluten components in some foods and even medicines. In this regard, a number of research groups and pharmaceutical companies are extensively developing alternative medicinal approaches to GFD for effective gluten intolerance treatment. This review summarizes our understanding of gluten-related disorders, possible mechanisms of gluten intolerance activation and advantages of gluten intolerance medicinal treatment using novel drug candidates obtained with a proper pharmaceutical design.