Current Drug Targets - Volume 19, Issue 5, 2018

Background: Osteosarcoma is considered the most frequent primary bone malignancy. Lung metastasis is the leading cause of death and the most consistent factor for predicting negative patient outcome in osteosarcoma. Third-generation nitrogen-containing bisphosphonates, such as zoledronic acid, have been shown to reduce osteolysis induced by bone metastasis and exhibit highly selective localization and retention in bone, thus making them attractive agents in the treatment of bone metastasis. Studies have shown that zoledronic acid exerts pleiotropic anti-tumor effects against osteosarcoma cells in vitro, including anti-proliferative, anti-angiogenic, and immunomodulatory effects. However, the efficacy of zoledronic acid against primary tumor growth and pulmonary metastasis of osteosarcoma is controversial, which has limited its clinical application. Objective: The present review summarizes the controversial effects of zoledronic acid on primary tumor burden and pulmonary metastases in osteosarcoma. We also analyze the clinical effectiveness of zoledronic acid alone and in combination with chemotherapeutic drugs for the treatment of osteosarcoma. Conclusion: Zoledronic acid exhibits diverse anti-tumor effects in osteosarcoma in vitro, however, the in vivo effect is still controversial. Further preclinical and clinical studies are needed to clarify the effects of zoledronic acid in osteosarcoma.

Background: Understanding the roles of miRNAs in osteoclasts has great potential in the diagnosis and treatment of osteolytic diseases. Objective: The purpose of this paper was to describe the current knowledge of miRNA biogenesis and summarize recent work on the roles of miRNAs in osteoclasts. Results: There is accumulating evidence to indicate that miRNAs constitute a novel and efficient mechanism for the regulation of gene expression. Conclusion: Untangling the role that miRNAs play in osteoclastogenesis will illuminate new strategies and specific drug targets for the treatment of osteolytic diseases. Many questions remain, but an in-depth comprehension of the network and kinetics of miRNAs expression, and their connection with cognate genes will not be trivial, but fruitful.

Background: The mitochondria may very well determine the final commitment of the cell to death, particularly in times of energy stress. Cancer chemotherapeutics such as the anthracycline doxorubicin perturb mitochondrial structure and function in tumour cells, as evidenced in osteosarcoma, for which doxorubicin is used clinically as frontline therapy. This same mechanism of cell inhibition is also pertinent to doxorubicin's primary cause of side-effects, that to the cardiac tissue, culminating in such dire events as congestive heart failure. Reactive oxygen species are partly to blame for this effect on the mitochondria, which impact the electron transport chain. Objective: As this review highlights that, there is much more to be learnt about the mitochondria and how it is affected by such effective but toxic drugs as doxorubicin. Conclusion: Such information will aid researchers who search for cancer treatment able to preserve mitochondrial number and function in normal cells.

Background: Vitamin C, traditionally associated with scurvy, is an important nutrient for maintaining bone health. It is essential in the production of collagen in bone matrix. It also scavenges free radicals detrimental to bone health. Objective: This review aims to assess the current evidence of the bone-sparing effects of vitamin C derived from cell, animal and human studies. Results: Cell studies showed that vitamin C was able to induce osteoblast and osteoclast formation. However, high-dose vitamin C might increase oxidative stress and subsequently lead to cell death. Vitamin C-deficient animals showed impaired bone health due to increased osteoclast formation and decreased bone formation. Vitamin C supplementation was able to prevent bone loss in several animal models of bone loss. Human studies generally showed a positive relationship between vitamin C and bone health, indicated by bone mineral density, fracture probability and bone turnover markers. Some studies suggested that the relationship between vitamin C and bone health could be U-shaped, more prominent in certain subgroups and different between dietary and supplemental form. However, most of the studies were observational, thus could not confirm causality. One clinical trial was performed, but it was not a randomized controlled trial, thus confounding factors could not be excluded. Conclusion: vitamin C may exert beneficial effects on bone, but more rigorous studies and clinical trials should be performed to validate this claim.

Background: Osteoporosis is a debilitating disease characterized by bone micro-architecture degradation contributing to fragility fractures. Currently, determining bone mineral density (BMD) via dual-energy X-ray absorptiometry (DXA) is the most reliable form of diagnosing osteoporosis and managing pharmacological treatment regimens. However, changes in BMD occur slowly (i.e., several months) and DXA does not reflect the metabolic rate of bone turnover. Alternatively, biochemical bone turnover markers are metabolic indicators released into serum and/or urine, and their quantity reflects the metabolic activity of bone. bone turnover markers show a rapid response following antiresorptive drug administration, and enzyme-linked immunosorbent assays (ELISA) have been established and used in clinical trials to help assess and predict fracture risk independent of BMD. Objective: This review highlights various established bone turnover markers that have found utility in the clinic as reliable and standardized indicators of bone turnover, with attention to those used to assess efficacy of bisphosphonate drug therapy – particularly in monitoring medication adherence in patients with postmenopausal osteoporosis. Results: We posit that the use of urinary bone turnover markers values determined by immunoassay or ELISA at routine clinic visits might serve as valuable feedback to healthcare professionals and patients to help monitor the efficacy and adherence of bisphosphonate therapy and disease progression. Conclusion: Our belief is that when assessed in combination with an algorithm of independent risk factors, measuring urinary bone turnover markers using a point of care kit may find utility in the osteoporosis clinic as an accessible, non-invasive and cost-effective alternative for the routine assessment of efficacy of bisphosphonate therapies.

Background: Chitosan-containing compounds have been shown to be suitable for bone replacement, but few studies demonstrate the impact of the chitosan as a free drug on the fracture.In this study, we aimed to evaluate possible effects of free chitosan on fracture healing. Materials and Methods: Thirty adult male Sprague-Dawley rats with a mean body weight of 205 g (range from 200g to 210g) were randomly and equally divided into two groups. Standardized femur fractures were created in all rats. Treatments were administered intraperitoneally twice weekly at 1 mg chitosan per injection and the controls were administered physiological saline. The site of the fracture was compared with the control group at 1, 2 and 4 weeks after surgery (n=5 in each group). The weight, activity and reaction of the rats were observed at all the timepoints. Anterior-posterior radiographs and micro-CT scans of all fractures were taken after surgery, and the parameters included: the volume of callus that was calculated using the Perkins volume formula, BV/TV, BV, BMD of cortical bone, cortical thickness, and cortical number at the fracture sites. After sacrifice, fractured femurs from rats were dissected and carefully cleaned of muscle around the fracture callus to preserve callus integrity. Sections were stained with haematoxylin and eosin for histological evaluation of healing. Result: Radiological (X-ray and micro-CT) evaluation showed that fracture healing of the experimental group was better than control group at the second week and fourth week. Histological evaluation revealed fracture healing of the experimental group was better than control group at the same time. There was no statistically significant difference in fracture healing between the two groups at the first week. Conclusion: Systemic delivery of free chitosan can accelerate the bone healing process in rat femur fracture at the early-middle stage.

Background: Bone defects can be severely debilitating and reduce quality of life. Osteoregeneration can alleviate some of the complications in bony defects. For therapeutic use in future, a single factor that can cause potent bone regeneration is highly preferred as it will be more costeffective, any off-target effects will be more easily monitored and potentially managed, and for ease of administration which would lead to better patient compliance and satisfaction. Objective: We demonstrate that pigment epithelium-derived factor (PEDF), one such factor that is known to be potent against angiogenesis, promotes osteoblastogenesis in mesenchymal stem cells in vitro, but does not need co-encapsulation of cells in alginate bead scaffolds for osteogeneration in vivo. Results: Osteogenic differentiation by PEDF in vitro was confirmed with immunoblotting and immunocytochemical staining for bone markers (alkaline phosphatase, osteocalcin, osteopontin, collagen I), calcified mineral deposition, and assay for alkaline phosphatase activity. PEDF-mediated bone formation in a muscle pocket in vivo model was confirmed by microcomputed tomography (microCT), histology (haematoxylin and eosin, Alcian blue staining), immunostaining for bone markers and for collagen I-processing proteins (heat shock protein 47 and membrane type I matrix metalloproteinase). Conclusion: PEDF therefore presents itself as a promising biological for osteogeneration.

Background: Osteosarcoma (OS) is a neoplastic condition afflicting mostly the young, as the lesion usually occurs in areas of bone growth with tumour cells metastasising to the lungs in advanced disease. There is no real cure for the disease, with conventional drugs causing side-effects that decrease the quality of life of sufferers. Newer and safer drugs are needed, and one avenue is to use natural compounds that can stunt the growth of the tumour. Objective: In this study, two such biological entities were evaluated: krill oil and fish oil. Human OS cells were exposed to krill oil, fish oil, EPA and DHA in time-course assays lasting up to 72h. Results: Krill oil inhibited 23, 50 and 64% of cell proliferation at 24, 48 and 72h respectively, while fish oil resulted in no significant changes although an increase was observed at 24h. Interestingly EPA and DHA promoted OS cell proliferation and migration in this neoplasia. The inhibitory effect of krill oil was comparable to 0.5 and 1μM doxorubicin, a commonly used clinical drug for OS treatment. Conclusion: These results indicate that krill oil may be used in combination with standard clinical practices to control primary tumour growth, and more importantly, metastasis.

Background: JAK/STAT signal pathway, a requisite part in the signaling process of growth factors and cytokines, has become attractive targets for numerous immune, inflammatory and hematopoietic diseases. Objective: Herein, we present a review of the JAK/STAT signal pathway, the structure, biological function, mechanism of the JAKs and STATs along with a summary of the up-to-date clinical or approved JAK inhibitors which are involved in the treatment of various kinds of tumors and other immunity indications. Moreover, kinds of recently discovered JAKs inhibitors with potent activity or promising selectivity are also briefly discussed. Conclusion: Research and development of isoform selective JAK inhibitors has become a hot topic in this field. With the assistance of high throughput screening and rational drug design, more and more JAK inhibitors with improved selective profiles will be discovered as biological probes and even therapeutic agents.

Background: The Plasmodium falciparum cysteine proteases, also known as falcipains, are involved in different erythrocytic cycle processes of the malaria parasite, e.g. hydrolysis of host haemoglobin, erythrocyte invasion, and erythrocyte rupture. With the biochemical characterization of four falcipains so far, FP-2 (falcipain-2) and FP-3 (falcipain-3), members of the papain-like CAC1 family, are essential haemoglobinases. They could therefore be referred to as potential anti-malarial drug targets in the search for novel therapies, which could ease the burden caused by the increasing resistance to current antimalarial drugs. Objectives: This review provides a summary of the most important results, highlighting the drug design approaches essential for the understanding of the mechanism of inhibition and discovery of inhibitors against cysteine proteases from P. falciparum. Results: Rational and computer-aided drug discovery approaches for the design of promising falcipain inhibitors are described herein, with a focus on a variety of structure-based and ligand-based modeling approaches. Moreover, the key features of ligand recognition against these targets are emphasized. Conclusion: This review would be of interest to scientists engaged in the development of drug design strategies to target the cysteine proteases, FP-2 and FP-3.

Background: Diabetic foot ulcers (DFUs) are the chronic, non-healing complications of diabetic mellitus which compels a significant burden to the patients and the healthcare system. Peripheral vascular disease, diabetic neuropathy, and abnormal cellular and cytokine/chemokine activity are among the prime players which exacerbate the severity and prevent wound repair. Unlike acute wounds, DFUs impose a substantial challenge to the conventional wound dressings and demand the development of novel and advanced wound healing modalities. In general, an ideal wound dressing should provide a moist wound environment, offer protection from secondary infections, eliminate wound exudate and stimulate tissue regeneration. Objective: To date, numerous conventional wound dressings are employed for the management of DFUs but there is a lack of absolute and versatile choice. The current review was therefore aimed to summarize and critically discuss the available evidences related to pharmaceutical and therapeutic viability of polymer-based dressings for the treatment of DFUs. Results: A versatile range of naturally-originated polymers including chitosan (CS), hyaluronic acid (HA), cellulose, alginate, dextran, collagen, gelatin, elastin, fibrin and silk fibroin have been utilized for the treatment of DFUs. These polymers have been used in the form of hydrogels, films, hydrocolloids, foams, membranes, scaffolds, microparticles, and nanoparticles. Moreover, the wound healing viability and clinical applicability of various mutually modified, semi-synthetic or synthetic polymers have also been critically discussed. Conclusion: In summary, this review enlightens the most recent developments in polymer-based wound dressings with special emphasis on advanced polymeric biomaterials, innovative therapeutic strategies and delivery approaches for the treatment of DFUs.

Background: Protein tyrosine phosphatase 1B (PTP1B) is an important therapeutic target for type II diabetes and obesity because of its pivotal role as a negative modulator in both insulin and leptin signalling pathways. Objective: The discovery of PTP1B inhibitors has been the focus of researchers in both academia and pharmaceutical industry over the last two decades. Results and Conclusion: Though, intense pharmaceutical research in this area has resulted in many potent PTP1B inhibitors, a vast majority of them possessed pTyr mimetic group such as phosphonates, carboxylic acids and sulphamic acids, which led to poor PTP1B selectivity and insufficient in vivo efficacy due to low cell permeability and bioavailability. The availability of X-ray crystallographic structures of PTP1B together with the application of molecular modelling and other innovative strategies led to the development of many potent and selective PTP1B inhibitors with desirable physicochemical properties. This review traces the development of PTP1B inhibitors over the last decade and also records novel PTP1B inhibitors developed recently with greater emphasis on their selectivity and cell permeability.