Current Medicinal Chemistry - Volume 27, Issue 39, 2020

Paclitaxel (PTX) is a first-line drug for late-stage non-small cell lung cancer (NSCLC) patients who do not benefit from targeted therapy or immunotherapy. However, patients invariably develop resistance to PTX upon prolonged treatments. Although diverse mechanisms leading to PTX resistance have been well-documented in the literature, strategies to overcome PTX resistance in NSCLC based on these mechanisms are still challenging. In this article, we reviewed recent advancements elucidating major mechanisms of PTX resistance in NSCLC, including the overexpression of ABC transporters, alternations to tubulin structures, and the involvement of cytokines, miRNAs, kinase signaling pathways, and epithelial-mesenchymal transition. Potential markers of PTX resistance or PTX response that could help to direct treatment decisions and restore cellular sensitivity to PTX were also discussed. Finally, we summarized the corresponding strategies to overcome PTX resistance in NSCLC cells, which might provide new insights into clinical trials and benefit lung cancer patients in the future.

The risk assessment of mercury (Hg), in both wildlife and humans, represents an increasing challenge. Increased production of Reactive Oxygen Species (ROS) is a known Hg-induced toxic effect, which can be accentuated by other environmental pollutants and by complex interactions between environmental and genetic factors. Some epidemiological and experimental studies have investigated a possible correlation between brain tumors and heavy metals. Epigenetic modifications in brain tumors include aberrant activation of genes, hypomethylation of specific genes, changes in various histones, and CpG hypermethylation. Also, Hg can decrease the bioavailability of selenium and induce the generation of reactive oxygen that plays important roles in different pathological processes. Modification of of metals can induce excess ROS and cause lipid peroxidation, alteration of proteins, and DNA damage. In this review, we highlight the possible relationship between Hg exposure, epigenetic alterations, and brain tumors.

Background: Hepatocellular Carcinoma (HCC) is one of the greatest global health burdens because of its uncontrolled cell growth and proliferation, aggressive nature as well as inherited chemoresistance. In spite of different treatment options currently available for HCC, the 5-year relative survival rates for HCC patients with regional and distant stages of the disease are still low, which highlights the urgent need for novel therapeutic strategies for HCC. Recent findings strongly suggest that specific lipid species, such as sphingolipids, play a prominent role in tumorigenesis. Objective: We will give an overview of recent literature findings on the role of ceramide metabolism in the pathogenesis and treatment of HCC. Results: HCC is characterised by dysregulation of ceramide metabolism, which could be ascribed to altered activity and expression of ceramide synthases 2, 4 and 6, and acid and alkaline ceramidases 2 and 3, as well as to deregulation of Sphingosine kinases (SphK) 1 and 2 and sphingosine-1- phosphate receptors, in particular, S1PR1. Among them, SphK2 has emerged as a clinically relevant drug target in HCC whose inhibition by ABC294640 is currently being investigated in a clinical trial in patients with advanced HCC. Another promising strategy includes restoration of ceramide levels in HCC tissues, whereby nanoliposomal ceramides, in particular C6-ceramide, has emerged as an effective therapeutic agent against HCC whose safety and recommended dosing is currently being clinically investigated. Conclusion: Development of novel drugs specifically targeting ceramide metabolism could provide an enhanced therapeutic response and improved survival outcome in HCC patients.

Triple Negative Breast Cancers (TNBC) are heterogeneous and aggressive pathologies, with distinct morphological and clinical characteristics associated with their genetic diversity, epigenetics, transcriptional changes and aberrant molecular patterns. Treatment with anti-neoplastic drugs exerts systemic effects with low specificity, and incipient improvement in overall survival due to chemoresistance and recurrence. New alternatives for TNBC treatment are urgent and parthenolide or its analogues have been explored. Parthenolide is a sesquiterpene lactone with promising antitumor effects against TNBC cell lines. This review highlights the importance of parthenolide and its analogue drugs in TNBC treatment.

The prevalence of Type 2 Diabetes Mellitus (T2DM) is internationally ever-growing. Therefore, prevention, diagnostics, and control of insulin resistance and T2DM are of increasing importance. It has been suggested that mechanisms leading to insulin resistance and diabetes and its complications include high intake of refined and energy-rich food, which is presumed to be accompanied by suboptimal intake of trace elements, such as Zinc (Zn), Selenium (Se), Chromium (Cr), and Copper (Cu), which are essential and crucial for various biological processes. The purpose of this review is to highlight the role of Zn, Se, and Cu in T2DM. Diabetes seems prevalent when Zn, Se, and Cu are deficient, which may result from excessive intake of refined food. The literature search was conducted in PubMed and Scopus, supplemented with the reference lists of relevant articles and a Google Scholar search. We critically assessed all relevant citations, both review and research papers in English. The search terms that were used included Zn, Cu, diabetes, and diabetes mellitus. Research has shown that Zn, Se and Cu are involved in the pathogenesis of diabetes, but these trace elements can in excessive amounts be toxic. Zinc appears to activate key molecules that are involved in cell signaling, which maintain the homeostasis of glucose. Zinc also regulates insulin receptors, prolong the action of insulin, and promote healthy lipid profiles. Copper in excess can create oxidative stress, which is a factor in the onset and the progression of T2DM. Abnormal Zn and Cu metabolism appears to accompany and may also cause diabetes complications.

Alzheimer’s Disease (AD) is a chronic and progressive neurodegenerative disorder that affects over 46 million people worldwide. It is characterized by a decline in cognitive abilities, including memory and thinking skills. AD patients also suffer from behavioral and psychological symptoms of dementia of which depression is the most prevalent. Currently available drugs provide modest symptomatic relief and do not reduce pathological hallmarks (senile plaques and neurofibrillary tangles) and neuroinflammation, both of which are integral parts of AD. Studies suggest that AD is a type of diabetes manifested in the brain. Although AD and diabetes are currently classified as separate disease entities, they share common pathophysiological mechanisms, one of them is an increased level of cytokines involved in the inflammation and the regulation of metabolic, regenerative, and neural processes. The purpose of this review was to update the most recent reports on the discovery and development of antidiabetic agents as promising drugs for the symptomatic and diseasemodifying treatment of AD. We collected the results of in vitro and in vivo studies, and recent reports from clinical trials suggesting the utility of antidiabetic agents in memory-enhancing therapy of AD. Their beneficial effects on chronic neuroinflammation, pathological hallmarks, and neuropsychiatric symptoms co-occurring with cognitive deficits are also presented. Antidiabetic agents refer to the diabetic and inflammatory hypotheses of AD and provide hope to find an effective drug for comprehensive therapy of the disease.

Type 2 diabetes mellitus (DM) is a public health burden and its co-existence with hypertension is long established in the context of the metabolic syndrome. Both DM and hypertension are major risk factors, for end-stage renal disease, cardiovascular events and mortality. Strict blood pressure (BP) control in diabetics has been associated with a cardiovascular and renal risk decrease. Inhibitors of the sodium-glucose co-transporter 2 (SGLT-2) in the proximal tubule is a relatively novel class of agents for the treatment of type 2 DM. Inhibition of SGLT-2 co-transporter combines proximal tubule diuretic and osmotic diuretic action leading to glucose reabsorption reduction and mild natriuretic and diuretic effects. On this basis, several studies showed that treatment with SGLT-2 inhibitors can effectively decrease hyperglycemia but also increase BP control and reduce renal outcomes and cardiovascular mortality. Based on such evidence, the recent guidelines for the management of type 2 DM now suggest that SGLT-2 inhibitors should be preferred among oral agents in combination with metformin, in patients at increased cardiovascular risk, chronic kidney disease or heart failure. This review summarizes the existing data from studies evaluating the effect of SGLT-2 inhibitors on BP, and its potential value for cardio- and nephroprotection.

Multiple Sclerosis (MS), an autoimmune disorder associated with spinal cord and brain, chiefly affects the white matter. Regarding the complexity as well as heterogenic etiology of this disease, the treatment of MS has been a challenging issue up to now. Researchers are working to develop new therapeutic strategies and drugs as complementary therapies. MS diagnosis significantly depends on the findings of Magnetic Resonance Imaging (MRI) examination. In this imaging technique, gadolinium is used as a contrast agent to reveal active plaques intending to destroy the bloodbrain barrier. It also detects plaques that are not correlated with the neurological symptoms. It has been attempted to determine biomarkers related to different dimensions of MS in various organizational hierarchy levels of the human anatomy (i.e., cells, proteins, RNA, and DNA). These biomarkers are appropriate diagnostic tools for MS diagnosis. In this review, we summarized the application of MRI and biochemical biomarkers to monitor MS patients. Moreover, we highlighted the joint application of MRI and biomarkers for the diagnosis of MS subjects.

Polycystic Ovary Syndrome (PCOS) is a common endocrine and metabolic disorder that affects women in their reproductive age. Recent studies have shown that genes have an important role in the etiology of PCOS. However, the precise way in which these genes are transcriptionally and post-transcriptionally regulated is poorly understood. The aim of the present review is to provide updated information on miRNAs and DNA methylation as epigenetic marks of PCOS. The data presented here allow concluding that both microRNAs and DNA methylation can be considered as possible useful biomarkers when choosing the treatment for a specific PCOS phenotype and thus represent two important tools for the diagnosis and treatment of PCOS patients.

The neuromedin U peptide sequence is highly conserved between various species. Neuromedin U is involved in a variety of physiological processes. It exerts its effects via two neuromedin U receptors, NMUR1 and NMUR2. These receptors are characterized by a distinct, yet complementary, tissue distribution with NMUR1 mostly found in the periphery, while NMUR2 is most abundant in the central nervous system. The capability of the neuropeptide to reduce food intake in rodents triggered the design and synthesis of a broad range of modified peptide ligands. The purpose of these ligands is to develop novel therapeutics which could be beneficial in the treatment of obesity and diabetes. Most compounds are derived either from the full-length neuromedin U sequence or are based on the truncated orthologs of this neuropeptide. Only a few non-peptidic ligands were developed. This review provides an overview on various neuromedin U analogs and mimetics that have been reported to date.