Current Molecular Pharmacology - Volume 11, Issue 3, 2018

Background: Each year, millions of people die from cancer. Radiotherapy is one of the main treatment strategies for cancer patients. Despite the beneficial roles of treatment with radiation, several side effects may threaten normal tissues of patients in the years after treatment. Discussion: Moreover, high incidences of second primary cancers may reduce therapeutic ratio of radiotherapy. The search for appropriate targets of radiosensitization of tumor cells as well as radioprotection of normal tissues is one of the most interesting aims in radiobiology. Cyclooxygenase-2 (COX-2), as an inflammatory mediator has attracted interests for both aims. COX-2 activity is associated with ROS production and inflammatory signs in normal tissues. These effects further amplify radiation toxicity in irradiated cells as well as adjacent cells through a phenomenon known as Bystander effect. Increased COX-2 expression in distant non-irradiated tissues causes oxidative DNA damage and elevated cancer risk. Moreover, in tumors, the activation of this enzyme can increase resistance of malignant cells to radiotherapy. Hence, the inhibition of COX-2 has been proposed for better therapeutic response and amelioration of normal tissues. Celecoxib is one of the most studied COX-2 inhibitor for radiosensitization and radioprotection, while some other inhibitors have shown interesting results. Conclusion: In this review, we describe the role of COX-2 in radiation normal tissue injury as well as irradiated bystander and non-targeted cells. In addition, mechanisms of COX-2 induced tumor resistance to radiotherapy and the potential role of COX-2 inhibition are discussed.

Background: Expression and activation of subtype-3 muscarinic receptors (M3R) plays an important role in the progression of colorectal neoplasia. Method: Herein, we describe the role of muscarinic receptors in colon cancer, focusing specifically on M3R, illustrate how M3R over-expression and activation of post-receptor signaling pathways potentiates tumor progression, and explore the efficacy and safety of a variety of therapeutic approaches that can target the molecules involved. Results: Colon cancers overexpress M3R mRNA (CHRM3) and protein, and post-M3R signaling stimulates cell proliferation. Post-M3R signal transduction is complex, involving interplay between epidermal growth factor receptors (EGFR)/ERK and protein kinase C (PKC)/p38 mitogen-activated protein (MAP) kinase signaling pathways. In particular, the development of an invasive and metastatic phenotype requires that these signaling interactions augment cellular release of a key collagenase, matrix metalloproteinase-1 (MMP1). Blocking either M3R activation or post-M3R signaling attenuates MMP1 release and colon cancer invasiveness. Conclusion: Parsing the complexities of these signaling interactions is important, not only to understand these mechanisms of cancer initiation and progression, but also to develop novel treatment modalities. Since the vast majority of persons with colon cancer die from disseminated disease, preventing or reversing metastatic spread of cancer cells by targeting M3R, post-M3R signaling, or MMP1 has therapeutic potential.

Background: Tyrosine-protein phosphatase is an enzyme that functions in a unit with tyrosine kinases to regulate signaling pathways. Several members of the PTP family link to human disease predisposition such as PTP1B, SH2, DEP1, and inhibition of these enzymes may represent an effective palliative therapy. Objective: This review aims to summarize the rapidly developing role of the PTPs in various physiological and pathological states. Results: Pharmacological inhibition of protein tyrosine phosphatase has been found to reduce endothelial dysfunction in different cardiovascular diseases related to metabolic disorders and it can be helpful for the management of other brain disorders associated with perhaps even in normal, agerelated cognitive decline. Tyrosine-protein phosphates have both stimulatory and inhibitory consequences on cancer-associated signaling pathways and deregulation of PTKs involves tumorgenesis. Conclusion: Inhibition of protein tyrosine phosphatase plays an important function in the improvement of various diseases such as metabolic, cardiovascular disorders, cancer and autoimmune disease.

Background: Inflammation is the response of the immune system that guards the body against several harmful stimuli in normal conditions. However, in response to ionizing radiation that leads to a massive cell death and DNA aberrations, this phenomenon causes various side effects in normal tissues. Inflammation is involved in various side effects such as gastrointestinal toxicity, mucositis, skin reactions, nervous system damage, pneumonitis, fibrosis and so on. Discussion: Observations have proposed that inflammatory mediators are involved in the toxic effect of ionizing radiation on non-irradiated cells via a phenomenon named bystander effect. Inflammation in both irradiated and non-irradiated cells can trigger genomic instability, leading to increased risk of carcinogenesis. Targeting the inflammatory mediators has been an interesting idea for improving the therapeutic ratio throughout the reduction of normal tissue injury as well as an increase in tumor response to radiotherapy. Conclusion: So far, various targets have been proposed for the amelioration of radiation toxicity in radiotherapy. Of different targets, NF-ΚB, COX-2, some of NADPH Oxidase subfamilies, TGF-β, p38 and the renin-angiotensin system have shown promising results. Interestingly, inhibition of these targets can help sensitize the tumor cells to the radiation treatment with some mechanisms such as suppression of angiogenesis and tumor growth as well as induction of apoptosis. In this review, we focus on recent advances on promising studies for targeting the inflammatory mediators in radiotherapy.

Background: Candida albicans is present as part of the normal gut flora and detected in the oral cavities and GI tracts of around fifty percent of adults. Benign colonization can turn pathogenic causing a variety of mild to severe infections. In a pathogen, the cell wall and cell surface proteins are major antigenic determinants and drug targets as they are the primary structures that contact the host. Cell surface proteins perform a variety of functions necessary for virulence such as adhesion, host degradation, resistance to oxidative stress, and drug resistance. We have previously characterized Hwp2, a C. albicans cell wall adhesin shown to play a major role in the cell wall architecture and function as hwp2 mutants were deficient in chitin deposition, filamentation, adhesion and invasive growth, virulence, and resistance to oxidative stress. Objective/Method: Here, we utilized tandem mass spectrometry coupled with a bioinformatics approach to differentially profile the cell wall proteome of a wild-type strain compared to an hwp2 null mutant to determine key differentially expressed proteins. Result: Many proteins identified exclusively in the wild-type go a long way in explaining the abovementioned phenotypes. These include virulence factors such as members of the SAP family including Sap4, Sap5, and Sap10, as well as several lipases involved in host degradation. We also identified members of the PGA family of proteins Pga28, Pga32, Pga41 and Pga50, which function in adhesion, Cht2 a chitinase involved in chitin remodeling, and several proteins that function in promoting filamentation such as Phr1, Mts1, and Rbr1.

Background: The Renin Angiotensin System (RAS) is pharmacologically targeted to reduce blood pressure, and patient compliance to oral medications is a clinical issue. The mechanisms of action of angiotensin receptor blockers (ARBs) in reducing blood pressure are not well understood and are purported to be via a reduction of angiotensin II signaling. Objective: We aimed to develop a transdermal delivery method for ARBs (losartan potassium and valsartan) and to determine if ARBs reveal a vasodilatory effect of the novel RAS peptide, alamandine. In addition, we determined the anti-hypertensive effects of the transdermal delivery patch. Methods: In vitro and in vivo experiments were performed to develop an appropriate therapeutic system, promising an alternative and more effective therapy in the treatment of hypertension. A variety of penetration enhancers were selected such as isopropyl myristate, propylene glycol, transcutol and dimenthyl sulfoxide to obtain a constant release of drugs through human skin. Small resistance vessels (kidney interlobar arteries) were mounted in organ baths and incubated with an ARB. Vasodilatory curves to alamandine were constructed. Results: The in vivo studies demonstrate that systemic absorption of valsartan and losartan potassium using the appropriate formulations provide a steady state release and anti-hypertensive effect even after 24 hours of transdermal administration. No apparent skin irritations (erythema, edema) were observed with the tested formulations. We also show that blocking the AT1 receptor of rabbit interlobar arteries in vitro reveals a vasodilatory effect of alamandine. Conclusion: This study reveals the potential mechanism of AT1 receptor blockade via alamandine, and is an important contribution in developing a favorable, convenient and painless antihypertensive therapy of prolonged duration through transdermal delivery of AT1 blockers.

Background: In age-related macular degeneration, oxidative damage and abnormal neovascularization in the retina are caused by the upregulation of vascular endothelium growth factor and reduced expression of Glutathione-S-transferase genes. Current treatments are only palliative. Compounds from cruciferous vegetables (e.g. L-Sulforaphane) have been found to restore normal gene expression levels in diseases including cancer via the activity of histone deacetylases and DNA methyltransferases, thus retarding disease progression. Objective: To examine L-Sulforaphane as a potential treatment to ameliorate aberrant levels of gene expression and metabolites observed in age-related macular degeneration. Method: The in vitro oxidative stress model of AMD was based on the exposure of Adult Retinal Pigment Epithelium-19 cell line to 200μM hydrogen peroxide. The effects of L-Sulforaphane on cell proliferation were determined by MTS assay. The role of GSTM1, VEGFA, DNMT1 and HDAC6 genes in modulating these effects was investigated using quantitative real-time polymerase chain reaction. The metabolic profiling of L-Sulforaphane-treated cells via gas-chromatography massspectrometry was established. Significant differences between control and treatment groups were validated using one-way ANOVA, student t-test and post-hoc Bonferroni statistical tests (p<0.05). Results: L-Sulforaphane induced a dose-dependent increase in cell proliferation in the presence of hydrogen peroxide by upregulating Glutathione-S-Transferase μ1 gene expression. Metabolic profiling revealed that L-Sulforaphane increased levels of 2-monopalmitoglycerol, 9, 12, 15,-(Z-Z-Z)- Octadecatrienoic acid, 2-[Bis(trimethylsilyl)amino]ethyl bis(trimethylsilyl)-phosphate and nonanoic acid but decreased β-alanine levels in the absence or presence of hydrogen peroxide, respectively. Conclusion: This study supports the use of L-Sulforaphane to promote regeneration of retinal cells under oxidative stress conditions.

Introduction: Addiction is a compulsive drug-seeking and drug-taking behavior. Reduction of high-risk behaviors can reduce the burden of addiction in society and can improve the overall prognosis of drug addiction. The aim of this study is to show that reduction of oxidative stress with socialization will reduce occurrence of high-risk behavior during addiction period. Method: Fifty-four male Sprague-Dawley rats were randomly divided into four groups: socialized, isolated, addicted socialized and addicted isolated. For inducing morphine dependence, rats received morphine (5 mg/rat/kg/day) for 14 days. Socialization was induced by putting two rats in a large cage for 14 days. On the other hand, isolation was induced by putting rats in separate small cages covered with black plastic for the same period. At the end of the study, rats were experimented with shuttle box for assessing avoidance memory and also tested with social interaction test to measure noveltyseeking behavior and anxiety level. Then, animals were sacrificed for neurochemical analysis. Brain was isolated to assess oxidative-stress (OS) indices such as malondialdehyde (MDA), glutathione and nitrite/nitrate in prefrontal cortex and hippocampus. Results: After 14 days of morphine injection, rats in socialized group had improved avoidance memory, increased anxiety levels and reduced novelty-seeking behavior. Furthermore, isolated rats had reduced glutathione and nitrite/nitrate, and higher MDA levels in prefrontal cortex and hippocampus as compared to socialized rats. Conclusion: Pair state had positive effect on OS indices in prefrontal cortex and hippocampus and results in the reduction of relapse and poor prognosis. Thus, OS plays an important role in alleviation of severity of addiction period.