Current Drug Targets - Volume 19, Issue 1, 2018

Background: Salvia displays diverse anticancer properties, which are attributable to their diterpene and phenolic contents. There is no comprehensive review on the anticancer diversity and molecular targets of Salvia components. Objective: We investigate the diversity and molecular targets of Salvia phytometabolites responsible for the prevention and treatment of cancer and sarcoma. Results and Conclusion: Traditional therapeutic knowledge suggests that Salvia species can be used to develop anticancer drugs. Lots of concerns have been raised for tanshinone (Tan) IIA and cryptotanshinone. Some Salvia compounds disturb cell cycle and induce apoptosis of tumor cells or enhance immune activities, while others inhibit the proliferation, invasion, angiogenesis, and metastasis, or reverse the multi-drug resistance of cancer cells. Salvia phytometabolites regulate most cancer hallmarks defined by Hanahan and Weinberg. The same class of phytometabolite could exert the anticancer activity via multiple pathways. ADME/T properties and pharmacokinetic bebaviors of some phytometabolites have been revealed. Fluorescent probes are powerful tools for screening substrates, inhibitors or inducers of drug metabolizing enzymes/transporters from Salvia phytometabolites. Omics platform will greatly help mining more potentially useful phytometabolites from Salvia plants. More Salvia plants have application potential in pharmaceutical industry and clinical cancer therapy.

Background: PARP inhibitors appear to offer a promising role in the accompaniment of many of the cytotoxic agents used in the present day to combat cancer proliferation in BRCA ½ deficient tumors. Current species of PARP inhibitors have yet to demonstrate a superior effect to that of existing therapies when administered as a single agent; however, they have appeared to amplify the effect of these existing chemotherapies when utilized together. This suggests that PARP inhibitors could play an effective maintenance role in current cancer-combating strategies. In the immediate future, PARP inhibitors may only be applicable to a select group of cancers (i.e., those caused by defective HR pathways), though research is emerging that could indicate an extension of applicability to HR proficient cancer types as well. For the time being, however, the current literature suggests that a viable PARP inhibitorchemotherapy hybrid targeting HR deficient cancers could be well on its way very soon. Objective: In this manuscript we explores the ongoing and the completed clinical trials for different PARP inhibitors. Conclusion: Since the approval of Olaparib by both FDA and EMA, further clinical trials continue to investigate the use of Olaparib and other PARP inhibitors. The anticipating outcome of these trials may clarify the benefit of PARP inhibitors in management of various BRCA mutated solid tumors.

Background: The cytochrome P450 (CYP) enzymes are membrane-bound hemoproteins that play a pivotal role in the detoxification of xenobiotics, cellular metabolism and homeostasis. Induction or inhibition of CYP enzymes is a major mechanism that underlies drug-drug interactions. CYP enzymes can be transcriptionally activated by various xenobiotics and endogenous substrates through receptor-dependent mechanisms. CYP enzyme inhibition is a principal mechanism for metabolism- based drug-drug interactions. Many chemotherapeutic drugs can cause drug interactions due to their ability to either inhibit or induce the CYP enzyme system. Predictions based on in silico analyses followed by validation have identified several microRNAs that regulate CYPs. Genetic polymorphisms and epigenetic changes in CYP genes may be responsible for inter-individual and interethnic variations in disease susceptibility and the therapeutic efficacy of drugs. Objective: The present review is a comprehensive compilation of cytochrome P450 structure, function, pharmacogenetics, pharmacoepigenetics and clinical significance. Conclusion: Knowledge about the substrates, inducers, and inhibitors of CYP isoforms, as well as the polymorphisms of CYP enzymes may be used as an aid by clinicians to determine therapeutic strategy, and treatment doses for drugs that are metabolized by CYP gene products.

Background: Type 2 diabetes mellitus (T2DM) has been a great burden to the world and it is urgent to develop new treatment strategies. Recently, many targets are currently available to aid in the drug discovery of this disease as our understanding of the pathophysiology of T2DM develops. Objective: This article is intended to provide a broad ranging overview of 14 prominent molecule targets being pursued for the treatment of diabetes in recent decade, with regard to their therapeutic rationale, small molecule modulators and application prospects. Result: These targets are roughly divided into three general areas that correlate with insulin secretion, act on the insulin sensitivity, and have an effect on the complications, and these three kinds of targets are all helpful for the treatment of T2DM. Considering the fact that the lack of insulin become the main problem with the progress of T2DM, these targets based on insulin secretion would be more promising. Conclusion: Most of these new and potential targets mentioned in article lack clinical data and may or may not come to fruition for the treatment of diabetes in the future. Hence, further studies will illuminate the potential for each drug targets, although it is clear that this will take a lot of time.

Background: Thymoquinone (TQ) is a bioactive phytoconstituent obtained from Nigella sativa (black seeds). It has promising potential in cancer prevention. Objective: Previous studies have shown that TQ can modulate signaling pathways responsible for cancer progression, thus enhancing the efficacy and improving the safety profile of clinically used anticancer drugs. Method: TQ acts on cell cycle and inhibits progression from G1 to S phase by targeting various proteins (cyclin D1, cyclin E, and p27). It also exhibits histone deacetylase (HDAC) inhibitory effects, targets p21 and Maspin, and induces pro-apoptotic gene, Bax and downregulates anti-apoptotic gene Bcl-2. Breast cancer (BC) is reported as one of the most common malignancies in women. Results: Despite the research and advancement, it remains one of the most common causes of cancer related deaths among women. Recent advancements in molecular screening of BC led to the identification of clinically challenging condition of triple negative breast cancer (TNBC). TNBC is characterized by the absence of targetable receptors viz. estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2) expressions. It is also characterized by reduced or absence of phosphatase and tensin homolog (PTEN) expression, a tumor suppressor gene having diverse functions including regulation of apoptosis, cell cycle, and metastasis. Conclusion: Since TQ has been reported to up-regulate several growth factors such as vascular endothelial growth factor (VEGF), EGF and PTEN expression, the present review article discusses the targeting potential of TQ for therapeutic intervention against such types of breast cancer.

Background: Idarucizumab, a humanized monoclonal antibody fragment acting as a specific antidote for dabigatran, is approved for reversing the dabigatran-associated possible bleeding from critical sites or bleeding persisting despite local post-procedure haemostasis. Moreover, it can also be applied to reverse the dabigatran anticoagulant activity in emergency surgery or in other invasive procedure at high risk of bleeding. Objective: In this study, we discuss idarucizumab in light of the available literature data by conducting extensive research in the PubMed, EMBASE and Cochrane Library on the topic, using idarucizumab, dabigatran and their combinations as Mesh terms, and focusing on high impact investigations. Results: Several studies have demonstrated the capacity of idarucizumab to reverse laboratory measures of dabigatran-associated coagulopathy, however its efficacy and safety in real world patients are still not very clear because of the scarcity of available data which should be assessed with an extensive post market surveillance. Conclusion: The introduction of idarucizumab as dabigatran antidote in clinical practice represents a useful tool for clinicians. The possibility to rapidly restore the anticoagulation activity of dabigatran makes its use simpler and more manageable.

Background: Polysaccharides are widely found in animals, plants and micro- organisms, and are closely related to various physiological functions. It is one of the four basic substances that constitute life activities. Polysaccharide has antitumor, antivirus, antioxidant, immune regulation and other biological activities. Objective: Because the polysaccharide has significant antitumor effect and small side-effects, it has become the focus of the current antitumor drug research. Results: Herein, the polysaccharide species with antitumor effect were summarized in recent years, and the antitumor activity mechanisms of polysaccharides were analyzed and discussed. Conclusion: Many polysaccharides have good antitumor activity, and they have broad application prospects.