Current Drug Targets - Volume 19, Issue 10, 2018

Background: Eurycoma longifolia is a well-documented herbal medicine that has gained widespread recognition due to its versatile pharmacological activities including anticancer, antimalarial, antimicrobial, antioxidant, aphrodisiac, anti-inflammatory, anxiolytic, anti-diabetic, antirheumatism and anti-ulcer. Plethora of in vitro and in vivo studies evidenced their excellent antiproliferative and anticancer efficacy against various types of human cancers. Objective: This review was aimed to critically analyze the therapeutic viability and anticancer efficacy of Eurycoma longifolia in the treatment of cancer and also to propose its molecular and translational mechanism of cytotoxicity against cancerous cells. Results: Among a range of medicinally active compounds isolated from various parts (roots, stem, bark and leaves) of Eurycoma longifolia, 16 compounds have shown promising anti-proliferative and anticancer efficacies. Eurycomanone, one of the most active medicinal compounds of Eurycoma longifolia, displayed a strong dose-dependent anticancer efficacy against lung carcinoma (A-549 cells) and breast cancer (MCF-7 cells); however, showed moderate efficacy against gastric (MGC-803 cells) and intestinal carcinomas (HT-29 cells). The prime mode of cytotoxicity of Eurycoma longifolia and its medicinal compounds is the induction of apoptosis (programmed cell death) via the up-regulation of the expression of p53 (tumor suppressor protein) and pro-apoptotic protein (Bax) and downregulation of the expression of anti-apoptotic protein (Bcl-2). A remarkable alleviation in the mRNA expression of various cancer-associated biomarkers including heterogeneous nuclear ribonucleoprotein (hnRNP), prohibitin (PHB), annexin-1 (ANX1) and endoplasmic reticulum protein-28 (ERp28) has also been evidenced. Conclusion: Eurycoma longifolia and its medicinal constituents exhibit promising anticancer efficacy and thus can be considered as potential complementary therapy for the treatment of various types of human cancers.

Background: Particulate matter directly emitted into the air by sources such as combustion processes and windblown dust, or formed in the atmosphere by transformation of emitted gases are the major contributors to air pollution that triggers a diverse array of human pathologies including lung cancer. The mortality in lung cancer is usually high as the disease is not symptomatic at its early treatable stage. Moreover, available methods for screening are costly and mainly rely on imaging techniques which lack sufficient sensitivity and specificity. Despite progress in the identification of biomarkers, gene mutation based approaches still face formidable challenges as the disease evolves from a complex interplay between environment and host. Therefore, identification of an epigenomic signature might be useful for early diagnosis with the potential to reduce the environmental-associated disease burden. Objective: The review discusses the utility of epigenomic signature in identification and management of the environmental-associated lung cancers. Conclusion: Non-invasive 'liquid biopsy' based epigenomic screening has recently emerged as a methodology which has potential to characterize tumor heterogeneity at initial stages. Epigenetic signatures (methylated DNA, miRNA, and post transcriptionally modified histones) known to reflect the vital cellular changes, circulate at higher levels in the individuals with lung cancer. These circulating biological entities are reported to be closely associated with the clinical outcome of lung cancer patients and thus strongly stand as the probable candidate to identify disease at an early stage and monitor treatment response, thereby, benefiting patients and improving their lives. However, for effective implementation of the strategy as “point-of-care” test for screening population-at-risk will require exhaustive clinical validation.

Background: Histone acetylation is an essential approach of post-translational modification (PTM) and a significant component of epigenetic regulation that is mediated by Bromodomainscontaining protein (BRDs). In recent years, many researchers have found that a variety of malignancy, inflammatory and other diseases occurrences and developments are associated with BRD4 expression disorders or dysfunction. Meanwhile, many inhibitors of the extra-terminal (BET) family have been reported in many papers. Objective: This review summarized those newly found BET inhibitors, their mechanism of action and bioactivity. Secondly, those compounds were mainly classified based on their structures and their structure-activity relationship information was discussed. Beyond that, every compound's design strategy was pointed out. Results and Conclusion: Herein, the recent advances reported were reviewed for discovering more excellent small molecule inhibitors. Currently, in addition to compound 4, compounds 7, 22 and 90, have also been into the clinical trial stage. In the view of the outstanding performance of BET inhibitors in anti-tumor, anti-inflammatory and anti-drug resistance, we believe that more and more BET inhibitors will become the new epigenetic therapy for cancer, inflammation and autoimmune disease in clinical practice in the near future.

Background: Capsaicin (8-methyl-N-vanillyl-6-nonenamide) is the substance responsible of the irritation caused by the contact of chili peppers with the skin or mucous membranes. This protoalkaloid acts by stimulating the transient receptor potential cation channel subfamily V member 1 (TRPV1), which is mainly expressed by nociceptive fibers of peripheral sensory neurons, but is also present in the central nervous system, and in some non-neuronal cells. Following the initial, intense neuronal excitation, a brief refractory period occurs. However, repeated and massive exposures to capsaicin can impair nociceptive fiber function for weeks or months. During this lapse of time, disorders related to the hyperreactivity of peripheral nociceptors are abolished or greatly reduced. Capsaicin has been utilized to treat several diseases of upper airways. Objective: The objective of this review was to report the latest findings on the use of Capsaicin in the treatment of upper airway diseases. Results: Capsaicin effectiveness has been proved in non allergic rhinitis. Some studies suggest that this substance may be also effective in nasal polyposis and in the burning mouth syndrome. No clear evidence has been obtained about its use in allergic rhinitis. Conclusion: To date, the use of capsaicin to treat upper airway diseases is still limited in clinical practice. This may originate by the lack of strong, conclusive evidences of its effectiveness, by the variety of therapeutic schemes used in literature, and finally by the unpleasant effects of the exposure to capsaicin, which are only partly relieved by the pretreatment with local anesthetics.

Background: Silk Fibroin (SF), a natural source material obtained from Bombyx mori, has been widely enlisted as biomaterial having outstanding mechanical properties. SF has been reported as one of the propitious bio-polymers for various drug delivery systems, as well as drug delivery vehicle. Objective: This review is a summary of comprehensive applications of silk fibroin in various drug delivery systems, and also to present the current opportunities and requirements by furnishing a definitive assessment on silk fibroin as a polymer. Results: SF has been reported as one of the propitious bio-polymers for various drug delivery systems, as well as drug delivery vehicle. SF is inestimable owing to its non-toxic and non-antigenic character, except for the firmness formation whilst being stored at lower temperature. Unlike other polymeric biomaterials, SF is regenerated in aqueous systems in defined temperature, pressure and pH, which is one of its major advantages in formulation. SF nanoparticles are also used to deliver proteins and peptides. Recently, SF has been used to deliver anti-cancer agents like paclitaxel, doxorubicin, floxuridine, and methotrexate, and including the natural product curcumin, has shown to elicit significant biological activity when compared to their conventional form. Interestingly, SF has shown to be a promising biomaterial for implantables and injectable drug delivery applications. Conclusion: In the present review, we have summarized the physical and chemical properties, biocompatibility and non-immunogenic characters of SF and its applications in various drug delivery systems.

Background: Radiotherapy is the most widely used treatment method for average and advanced lung cancer patients. Moreover, the clinical toxicities caused by radiotherapy are categorized into acute radiation pneumonitis and late pulmonary fibrosis. Epithelial-mesenchymal transition (EMT) is a complex physiological process involves many signaling molecules and proteins like adaptor proteins, and transcriptional factors. It was identified as a significant mechanism for fibrosis, wound healing and also cancer. A variety of biomarkers have appeared in radiation-induced lung EMT, some of which are acquired (N-cadherin, vimentin and fibronectin, etc.) and some of which are repressed during the transition of epithelial cells (E-cadherin, zona occludens-1). Objective: In the current review, we highlighted the radiation-induced lung EMT signaling pathway and their mediators. We also discuss the EMT in cancer, fibrosis and its epigentics. Results: Radiation-induced lung EMT is controlled by numerous signaling pathways like MAPK, NF- ΚB, Wnt, microRNAs and histone modifications. Transcriptional factors such as Snail, slug, twist, ZEB1 (Zinc finger E-box binding-1) and ZEB2 (Zinc finger E-box binding-2) proteins are inducers linking radiation-induced EMT and fibrosis. Epigenetic modulations are heritable changes in the structure and function of the genome that occurs without any change in the sequence. Several approaches showed the role of epigenetic modifications and its inhibitors in controlling fibrosis and cancer. Only limited reports are focused on understanding the epigenetic regulations of radiation-induced lung EMT. Conclusion: The current review focused on recent findings regarding radiation-induced lung fibrosis and EMT, thus provides some information on important signaling pathways, its subsequent expression of genes and proteins involved in EMT. This review also discussed various inhibitors that could be used to treat EMT related diseases, i.e., fibrosis, cancer.

Background: Defects in DNA repair pathways are causal factors for a plethora of solid tumours, but are only just beginning to be explored in haematological malignancies. Genomic instability, including mutations in DNA sequences, chromosomal aneuploidy, translocations and gene amplifications contribute to the development and progression of AML. Prior DNA damaging agent exposure enhances the risk of developing AML, as does inheritance of genetic syndromes that involve alterations in DNA repair pathways. Furthermore, these same variations are associated with sensitivity and resistance to a range of chemotherapeutics. Taken together, these studies suggest that defects within DNA repair pathways are involved in the pathogenesis and prognosis of AML. Objective: This review summarises the major DNA repair pathways, and presents an overview of current data on DNA damage repair abnormalities in AML as they pertain to the development of resistance and sensitivity to chemotherapeutics in AML. Additionally, the use of drugs that modulate these pathways as new treatments for AML will be explored herein. Conclusion: This review highlights that abnormalities in DNA repair mechanisms in AML cells are potential novel treatment targets for AML patients with disease that is resistant to current therapies.

Single nucleotide polymorphisms (SNPs) in non-coding RNAs (ncRNA) molecules affect gene and protein expression and generate genetic variability influencing the risk of tumor diseases. HOTAIR locates at the heart of the cell memory gene program and represents a prototype of long non coding RNA (LncRNA) due to its capacity to regulate in-trans a distant chromosome landscape. Aberrant expression of HOTAIR is frequently associated with pathogenesis and mostly with metastatic progression of several human cancers. Different polymorphisms, particularly present in intronic sequences, as well as in promoter regions of HOTAIR, are often associated with its aberrant expression, patient prognosis, and cancer susceptibility in different tumor phenotypes. In this minireview, we have summarized the main SNPs in HOTAIR sequence and their relation with cancer risk in several types of solid tumors.