Current Drug Targets - Volume 18, Issue 10, 2017

Mammalian reproduction is a complex phenomenon. Human fertility is highly impacted from environmental exposure to toxicants as well as nutrients. The burden of environmental stimuli is heavy and multifaceted. The contaminant sources are many, often occult, and at present, the wide range of positive and negative consequences on the ecosystem and the human health is only partially understood. Compounds deriving from industrial manufacturing, pesticides, waste accumulation and burning are only some examples of the contaminants daily impacting human life. Ovary and testis biology, primordial germinal cells and gametogenesis are primary targets of a large number of pollutants. Pregnancy holds the basis of the healthy post-natal life of each individual and his offspring. During the pre-natal development, genetic and epigenetic factors concur to determine the good sequence of events for the good final outcome of the pregnancy. Worldwide epidemiological studies and focused experiments in animal models are unraveling the molecular basis of the normal and abnormal development. Evidences are growing about the relationship between pregnancy conditions and the onset of metabolic and other complex diseases in adult life. Epigenetic mechanisms, including DNA methylation, histone marks and non coding RNAs, are main molecular players of normal development and of the adaptive response during pre- and post-natal life.

Background: Ovarian cancer is the leading cause of deaths attributable to gynecologic malignancies. Late diagnosis and a high tendency of metastasis and drug resistance often lead to recurrence and poor outcomes. Anti-angiogenesis is considered a promising therapeutic strategy for recurrent ovarian cancers. Anti-VEGF body, bevacizumab, is an angiogenesis inhibitor with demonstrated activity and tolerable toxicity. Objective: To elucidate the benefits and side effects of bevacizumab for the therapy of recurrent ovarian cancer. Methods: Reviewed the results of published clinical trials. Results: Recent Phase II studies indicated that bevacizumab monotherapy or in combination with conventional or other anti-angiogenic chemotherapy reagents could be effective for recurrent (platinum- sensitive and -resistant) ovarian cancers. Additionally, two phase III randomized trials reached similar conclusions that in either platinum-sensitive or -resistant ovarian cancers, adding bevacizumab to chemotherapy can improve progression-free survival. Despite the general recognition of bevacizumab as a well-tolerated drug in recurrent ovarian cancer patients, oncologists have become aware of the significant risks associated with gastrointestinal perforation. Conclusion: Bevacizumab used alone or combined with other chemotherapy reagents is efficacious and tolerable in the treatment of recurrent ovarian cancer.

Immunity is a balanced status with adequate biological defenses to recognize and fight “non-self”, as well as adequate tolerance to recognize “self”. To maintain this immune homeostasis, a well-organized T cell immune network is required, which in part depends on the well-controlled development of alternative effector T cells, with different cytokine repertoires. Recent researches have pointed that developing fetal T cells network is a remarkably sensitive toxicological target for adverse factors in early life. Epidemiological and experimental studies showed an inseparable relationship between T cell developmental toxicity and immune diseases in adults. Considering that the inflammatory and immune disorders have become a growing health problem worldwide, increasing attention is now being paid to the T cell developmental toxicity. We propose that adverse factors may have programming effects on the crucial functions of immune system during early life which is critical for fetal T cell development and the establishment of the distinct T cell repertoires balance. The permanently disturbed intrathymic or peripheral T cell development may in turn lead to the immune disorders in later life. In this manuscript, we reviewed how adverse factors affected T cell development in early-life with the consequence of the immune dysfunction and immune diseases, and further elucidate the mechanisms. These mechanisms will be helpful in prevention and treatment of the increased prevalence of immune diseases by interfering those pathways.

Background: The CCAAT/enhancer binding proteins (C/EBPs) form a family of transcription factors regulating many genes’ expression in a variety of cells/tissues/organs at different developmental stages. With their capability of binding to their cognate DNA elements and through protein-protein interactions, C/EBPs modulate diverse functions including cell differentiation, metabolism, and immune response, under both physiological and pathological conditions such as the establishment of hematological lineages, the maintenance of normal reproductive function, and the development of malignancies. Objectives: This review concentrates on the role(s) and epigenetic alterations of C/EBP genes in hematologic malignancies and gynecologic organs and disorders. New research findings on molecular pathways involved in C/EBP function and regulation are reviewed and analyzed. The potential therapeutic values of these findings are also discussed. Conclusion: Unlike in hematologic malignancies in which C/EBP mutations and their disruption of wild type C/EBP tumor suppressive activities have been well documented, mutation of C/EBP does not appear to be a common event in gynecologic cancers, raising some doubt if C/EBPs may have tumor suppressor activity in gynecologic cancers. However, this notion could not exclude the possibility that downregulation or DNA methylation-meditated epigenetic silencing of C/EBPs may contribute to the development of gynecologic malignancies.

SET (SE translocation, SET) is an evolutionarily conserved gene broadly expressed in various human tissues, especially in the gonadal and neural system. As a multitasking protein, SET is involved in essential cell processes such as histone modification, chromatin remodeling, DNA repair, gene transcription, and androgen synthesis. Recent studies showed that SET is overexpressed in breast cancers, ovary cancers and a variety of other malignancies. The strong correlation between SET expression levels and survival of ovarian cancer patients, and SET-mediated activation of androgen synthesis, strongly indicated that this factor may play a significant role in gynecologic cancers. Here, we summarized data pertaining to the pathological implications of SET in tumorigenesis and cancer progression. We analyzed how SET, through the PP2A-dependent and PP2A-independent pathways, may regulate different cell functions. Potential interactions among these pathways and future studies on SET’s oncogenic activities are also discussed.

Background: HE4 may be a valuable early indicator of the recurrence of gynecologic cancers. Numerous studies have shown that high expression levels of serum HE4 correlate with ovarian and endometrial cancer recurrence. High HE4 levels may be an independent factor to predict these cancers’ poor prognosis. Objective: This literature review investigates the relationship between serum HE4 levels and the recurrence of ovarian and endometrial cancer. Conclusion: HE4 displays malignant behavior by promoting cancer cells to skip from G1 phase to S phase, maintaining cell viability, encouraging cell proliferation, inhibiting cell apoptosis, and increasing resistance to drug treatments. Further studies are required to verify that elevated serum HE4 levels correlate with the recurrence of ovarian and endometrial cancer.

Background: Preeclampsia, a gestational disease characterized by hypertension and proteinuria twenty weeks into pregnancy, is one of the leading causes of fetal and maternal mortality. Although multiple genetic and environmental factors are found to be related to the preeclampsia risk, the pathogenic pathways remain largely undefined. The placenta plays a critical role in the fetal development by carrying out the barrier, fetal-maternal exchange, and endocrine functions during pregnancy. Accumulated data indicated that the expression of multiple long noncoding RNA (LncRNA) is dysregulated in preeclamptic placentas. Moreover, manipulation of LncRNA expression led to functional alterations in trophoblast cell cultures, including changes in proliferation, differentiation, apoptosis, and migration. Objective: This article reviews published data on this subject and provides detailed information on the regulation and function of LncRNAs IGF2/H19, MEG3, SPRY4-IT1, HOTAIR, MALAT1, and FLT1P1 and CEACAMP8 in placental trophoblasts. The potential mechanisms underlying the action of these LncRNAs are also discussed to facilitate a better understanding on the potential role of these LncRNAs for the pathogenesis of preeclampsia. Conclusion: It is elaborated that some lncRNAs probably contribute to the pathogenesis of preeclampsia through methylation, Notch-EGFL7 signaling pathway and Wnt/β-catenin pathway.

Specific blocking of interactions between ligands and receptors along the angiogenic pathways represents an effective approach for enhancing the efficacy as well as reducing adverse effects of chemotherapy. Over the past decade, there was a rapid progression in the application of this therapeutic strategy in cancer treatment. Anti-angiogenic therapy is the most promising targeted therapy for ovarian cancer. The addition of bevacizumab to conventional chemotherapy, either in the first-line setting or at disease relapse, may improve overall survival (OS) of ovarian cancer patients, at least in a subset of patients with poor prognosis. In this article, we summarize published data on the major agents used for anti-angiogenic therapy in ovarian cancers. We will review the molecular mechanisms, results of clinical trial of existing agents and describe the development of new agents. The limitations and side effects of angiogenesis inhibitor are also discussed.

Background: Cholinergic transmission loss is one of the major features in Alzheimer's Disease (AD). Acetylcholinesterase inhibitors (AChEI) are moderately active in AD. α7nAChR (alpha-7 nicotinic acetylcholine receptor), encoded by CHRNA7 (Nicotinic Cholinergic Receptor Alpha-7 gene), is involved in the cholinergic neurotransmission and AD pathogenesis. α7nAChR is a putative receptor of amyloid beta (Aβ). The complex α7nAChR-Aβ is found in neuritic plaques and AD cortical neurons. In normal physiologic conditions, α7nAChR-Aβ interaction leads to receptor activation. Genetic polymorphisms (SNPs) of CHRNA7 and/or CHRFAM7A (fusion gene containing CHRNA7 partial duplication) may be a possible susceptibility trait to dementia, potentially useful to identify high risk or responder individuals. CHRFAM7A-2-bp deletion or CHRNA7 SNPs (rs1514246, rs2337506, rs8027814) seem protective factors in different forms of dementia including AD. Objective: Correlation between(SNPs) of CHRNA7 and/or CHRFAM7A and cholinesterase inhibitors in AD. Methods: Literature review. Results: Among the leading AD therapeutics, Donepezil (DP) and galantamine (AChEI) induce upregulation of α7nAChR protein levels, protecting neurons from degeneration. Patients carrying rs8024987 (C/G) or rs6494223 (C/T) respond better to AChEI. In the caucasic population rs6494223 TT subjects are 7-15% of the total. α7nAChR upregulation induced by DP is higher in lymphocytes from TT subjects than in CC or CT as well as calcium uptake. Conclusion: The correlation between genetic and functionality data may have an impact on several aspects of disease presentation and therapy, helping in prediction pattern of AD presentation and treatment efficacy. As a consequence it may lead to better patients quality of life and longer periods of self- sufficiency. Moreover, it may contribute to clarify AChEI mechanisms of action.

Background: Pulsatile drug delivery system (PDDS) shows potential significance in the field of drug delivery to release the maximum amount of drug at a definite site and at specific time. PDDS are mainly time controlled delivery devices having a definite pause period for drug release, which is not affected by acidity, alkalinity, motility and enzymes present in the gastrointestinal tract. Pulsatile medication possess the potential to deliver the drugs in the therapy of diseases where drug dose is essential during sleep, drugs having greater first pass metabolism and absorption at precise location in digestive tract. Objective: The review article, discuss the general concepts, marketed formulations and patents or any other recent advancement in pulsatile release technology. It also highlights on diseases requiring therapy by pulsatile release, various researches on herbal pulsatile formulations and quality control aspects of PDDS. Conclusion: Pulsatile medication possess the potential to deliver the drugs in the therapy of diseases where drug dose is essential during sleep, drugs having greater first pass metabolism and absorption at precise location in digestive tract.

Background: Renal cell carcinoma (RCC) accounts for 2% of all adult malignancies and is associated with a case fatality rate as high as 40%. RCC has been on the rise for the last 6 decades at a steady increase of 2% per annum. Much work has been done to uncover the pathogenesis of the disease and the role of angiogenesis has been a recurrent denominator connected to vascular endothelial growth factor (VEGF) and its downstream effectors along with the mammalian target of rapamycin (mTOR) mediated signal transduction pathway. Objective: This review will discuss relevant inhibitors of key biomarkers to the disease in hopes of paving the way for novel treatments geared towards improving RCC morbidity and mortality rates. Results and Conclusion: Currently, treatment of advanced RCC includes one or more of the following: partial or radical nephrectomy, systemic therapy, immunotherapy and targeted therapy. Still drug resistance continues to be a challenge to many of the approved drugs and those undergoing clinical trials. However, the inclusion of targeted therapies has improved advanced RCC treatment success rates over that of surgery alone, and over that of the use of traditional chemotherapy for this relatively chemo-resistant disease. In an era of personalized medicine, research utilizing a polypharmacology approach could enhance efficacy of drug leads to treating RCC.

Tankyrases belong to a group of enzymes called poly ADP ribosyl polymerases (PARPs). With the advent of a new class of small molecule inhibitors of PARP for clinical use like OLAPARIB; that gained accelerated approval by the USFDA in treating ovarian and breast cancers, the horizons of the PARPs as a novel target in various disease conditions has risen. Tankyrases (PARP 5) are yet another class of PARPs that perform poly ADP ribosylation on different substrate proteins aiding in progression of many diseases like cancer, fibrosis, diabetes and neurological disorders even. Few of the substrates of Tankyrases are Telomeric Repeat binding Factor protein (TRF1), Axis Inhibitory protein (AXIN 1&2), Insulin Responsive Amino Peptidase (IRAP), Nuclear Mitotic Apparatus protein (NuMa), that become aberrantly active due to the apparent overexpression of the enzyme during hyper proliferative disease conditions like cancer, fibrosis and metabolic disorders like diabetes. Tankyrases intervene in many physiological processes like cell growth and survival by affecting the Wnt signaling pathways. On the other hand, these functions are overdone during cancer and fibrosis especially. The development of novel therapies for cancer is a never ending process pertaining to several issues associated with current anticancer drugs like development of drug resistance and toxicity. A fibrotic disease like lung fibrosis is a debilitating condition with limited treatment options and survival rate. Tankyrase inhibition by specific small molecule inhibitors can therefore become a good combinatorial or single treatment strategy in treating hyper proliferative diseases and diabetes. In light of all these concerns, this article aims to brief the role of Tankyrase and the relevance of its inhibition to overcome the hurdles faced by current treatment regimens.