Current Drug Targets (v.15, #10)

Efficient drug delivery systems are exceedingly important for novel drug discovery. The evidence-basedpersonalized medicine (EBPM) promises to deliver the right drug at the right time to a right patient as it covers clinicallysignificantgenetic predisposition and chronopharmacological aspects of nanotheranostics. Recently nanotechnology hasprovided clinically-significant information at the cellular, molecular, and genetic level to facilitate evidence-based personalizedtreatment. Particularly drug encapsulation in pegylated liposomes has improved pharmacodynamics of cancer, cardiovasculardiseases, and neurodegenerative diseases. Long-circulating liposomes and block copolymers concentrateslowly via enhanced permeability and retention (EPR) effect in the solid tumors and are highly significant for the drug deliveryin cancer chemotherapeutics. Selective targeting of siRNA and oligonucleotides to tumor cells with a potential toinhibit multi-drug resistant (MDR) malignancies has also shown promise. In addition, implantable drug delivery deviceshave improved the treatment of several chronic diseases. Recently, microRNA, metallothioneins (MTs), α-synuclein index,and Charnoly body (CB) have emerged as novel drug discovery biomarkers. Hence CB antagonists-loaded ROSscavengingtargeted nanoparticles (NPs) may be developed for the treatment of neurodegenerative and cardiovascular diseases.Nonspecific induction of CBs in the hyper-proliferative cells may cause alopecia, gastrointestinal tract (GIT) symptoms,myelosuppression, neurotoxicity, and infertility. Therefore selective CB agonists may be developed to augment cancerstem cell specific CB formation to eradicate MDR malignancies with minimum or no adverse effects. This reviewhighlights recent advances on safe, economical, and effective treatment of neurodegenerative diseases, cardiovascular diseases,and cancer by adopting emerging nanotheranostic strategies to accomplish EBPM.

Chemoresistance in High-Grade Gliomas: Relevance of Adenosine Signalling in Stem-Like Cells of Glioblastoma Multiforme by Wallys Garrido, Jose Dellis Rocha, Catherinne Jaramillo, Katia Fernandez, Carlos Oyarzun, Rody San Martin, Claudia Quezada (931-942).
Glioblastoma multiforme (GBM) is the most common glial cell-derived brain tumour, with one of the worstprognoses among all cancers. GBM cells are infiltrative and extremely resistant to radio- and chemotherapy, which inevitablyleads to recurrence after surgical resection. These inherent GBM properties are the reasons that patient treatment hasnot seen major improvements in decades. Studies have consistently shown that glioblastoma stem-like cells (GSCs) areresponsible for the tumourigenic properties in the GBM population. In fact, their self-renewal and proliferative potentialare required for tumour growth, and their extreme chemoresistance leads to early recurrence of this tumour. Among thosemechanisms associated with chemoresistance and having the greatest clinical impact in cancer treatment, are the activitiesof plasma membrane transporters that extrude antitumour drugs from the cell, thus notably decreasing the pharmacologicalefficiency of these drugs. The multiple drug resistance associated protein-1 (Mrp1) transporter has been shown to beparticularly important in GBM, as inhibition of Mrp1 activity notably chemosensitises cells to antiproliferative drugs. Ascurrent therapeutic options for GBM offer only a poor improvement in overall survival rate, alternative strategies forovercoming tumour resistance are urgently sought after. To this end, it is of major clinical relevance to know more aboutthe endogenous modulators that control Mrp1 expression within the pathological environment of the tumour. This reviewdescribes the particular properties of glioblastoma cells that overcome multimodal therapy and relapse, with an emphasison the microenvironmental tumour properties that influence the chemoresistance phenotype to antiproliferative drugs. Wealso discuss alternative methods of reversal of Mrp1-mediated chemoresistance in these cells by targeting extracellularadenosine production or signalling through particular plasma membrane receptors.

Treatment of the Motor and Non-Motor Symptoms in Parkinson's Disease According to Cluster Symptoms Presentation by Fulvio Lauretani, Antonio Saginario, Gian Paolo Ceda, Laura Galuppo, Livia Ruffini, Anna Nardelli, Marcello Maggio (943-947).
The term Parkinson's disease has been changed in 'Parkinson's diseases' to describe different clinical entitiesobserved in several studies investigating the existence of PD subtypes. PD patients could be grouped based on clinical features.By considering only motor symptoms, we can classically distinguish two groups: “ the tremorigen-form” and “akinetic-rigidity-form” where resting tremor and akinesia/bradikynesia and rigidity are the most motor predominant symptoms,respectively. Non-motor symptoms (NMSs) are practically always present during the course of the disease and someof them (constipation, depressive status, hyposmia and anxiety) could even exist before the onset of classical motor symptoms.Many other NMSs and in particular hallucinations, cognitive impairment, sleep disorders and difficulty in swallowingstrongly affect the advanced stage of disease, and represent a real therapeutic challenge when these symptoms are simultaneouslypresent with different severity. If not adequately treated, they can increase the risk of hospitalization andadmissions in nursing home, and profoundly and negatively influence the quality of life and participation in social activityof these patients. PD subtypes according to the combination of motor and non-motor symptoms have been recently proposed.This classification derives from cluster analysis which permits to identify statistically distinct subtypes of Parkinsonianpatients according to the relevance of both motor and non-motor symptoms. In this point of view, we propose aschematic therapeutic approach of motor and non-motor symptoms in Parkinson's disease according to cluster symptomspresentation (motor and non-motor symptoms) and using medications that act on multiple domains of PD symptoms.

Mitochondrial aldehyde dehydrogenase (ALDH2) is an isoenzyme of aldehyde dehydrogenases (ALDH), agroup of enzymes that are responsible for clearance of aldehydes in the body. In animal myocardial or cerebral ischemia/reperfusion (I/R) models, accumulation of toxic aldehydes, such as 4-hydroxy-2-nonenal and malondialdehyde, isthought to be an important mechanism for myocardial and cerebral I/R injury. Among the isoenzymes of ALDH, ALDH2is believed to play a major role in clearance of toxic aldehydes. Thus, ALDH2 might be a potential drug target for protectionof the heart or brain from I/R injury. Indeed, some of the newly identified ALDH2 activators (such as Alda-1) havedemonstrated beneficial effects on heart and brain I/R injury. In addition, ALDH activity is present at high levels in somestem or progenitor cells, known as ALDH bright (ALDHbr) cells, which possess potential value in treating patients withmyocardial ischemia. The main purpose of this review is 1) to summarize recent findings regarding the role of ALDH2 inprotection of heart or brain from I/R injury, 2) to list the available ALDH2 activators with their potency, selectivity andclinical potentials, and 3) to provide a rationale for ALDHbr cells in clinical therapeutic value.

β-Adrenergic Over-Stimulation and Cardio-Myocyte Apoptosis: Two Receptors, One Organelle, Two Fates? by Ana F. Branco, Ana C. Moreira, Teresa Cunha-Oliveira, Renata Couto, Vilma A. Sardao, Albert A. Rizvanov, Andras Palotas, Paulo J. Oliveira (956-964).
Neuro-hormonal regulation of cardiac function via cathecol-amines results in increased heart rate and contractility.A persistent adrenergic tone, however, is an insult to the heart, affecting its regular homeostasis, altering morphologyand gene expression patterns, as well as inducing apoptosis of cardio-myocytes. At the same time as being the mainoxygen consumers, mitochondria are also key to the energy production required for the heart to maintain its vital functionsand to integrate a series of signaling pathways that define the life and death of the cell. As α-adrenergic receptors (α-AR)orchestrate multiple biochemical events that can either trigger or inhibit cell death, mitochondria can act as a referee in theentire process. In fact, α-AR subtypes α1 and α2 activate various down-stream pathways which differently modulate intracellularcalcium levels and production of mitochondrial reactive oxygen species (ROS). The delicate balance between anadaptive (cardio-protective) response resulting in increased contractility and activation of survival pathways, vs. cell deathcaused by calcium and ROS-induced mitochondrial disruption, along with evidence of their clinical and potential therapeutictranslations, are reviewed in this communication.

Circulating Tumor Cells (CTCs) as a Liquid Biopsy Material and Drug Target by Liang-Liang Cai, Hui-Ming Ye, Li-Mou Zheng, Run-Sheng Ruan, Chi-Meng Tzeng (965-972).
Circulating tumor cells (CTCs) have attracted interest as biomarkers of cancer metastases but only recently hasa reliable method of CTC detection been developed. CTCs can be thought of as a liquid biopsy from the blood, and theycan be used in pathological and molecular assays. CTCs may ideally replace metastatic tissue biopsies in the predictionand monitoring of therapeutic responses and tumor recurrence. CTCs can be used to guide therapeutic cancer managementand serve as drug targets. For this reason, the potential of this technology and the limitations of currently available methodsof CTC detection are addressed here. The clinical applications of CTCs include the prediction of cancer prognosis; selectionand monitoring of therapeutic regimens; and drug target applications. The manner in which CTC molecular profilingcan facilitate prognosis and the selection of cancer therapies.

Role of Prolyl Isomerase Pin1 in Pathogenesis of Diseases and Remedy for the Diseases from Natural Products by Katsuhiko Takahashi, Taiki Shimizu, Keita Kosaka, Masafumi Hidaka, Chiyoko Uchida, Takafumi Uchida (973-981).
The peptidyl prolyl cis/trans isomerase Pin1, the human ortholog of yeast Ess1 specifically isomerizes peptidebindings of pSer/pThr-Pro residues in various proteins, and regulates the expression levels and functions of phosphorylatedproteins. Activation of Pin1 is associated with pathology of a variety of diseases, such as cancer, Alzheimer's disease,infectious diseases and so on. Therefore, regulatory compounds for Pin1 can be applied as a clinical medicineagainst these diseases. Many chemists have exerted themselves to synthesize the inhibitors based on the 3D structure ofPin1. We have screened for the inhibitors against Pin1 from the natural products including the functional foods. Here wereview the Pin1-associated pathology and the known inhibitors identified from natural products. And we introduce thescreening methods targeting Pin1 activity.

PAF Receptor and Tumor Growth by Sonia Jancar, Roger Chammas (982-987).
The receptor for the lipid mediator PAF (PAFR) is a G-protein coupled receptor expressed in several cell types.Besides PAF, a series of oxidized phospholipids can also bind to PAFR. Dying cells also express PAFR-ligands and, inboth situations, scavenger receptors are involved as well. There is evidence that the scavenger receptor CD36 and PAFRassociate in the macrophages membrane and signal in conjunction to induce a regulatory phenotype. In the tumor microenvironment,apoptotic cells are abundant due to hypoxia, and PAF-like phospholipids are generated. Engagement ofPAFR expressed by tumor macrophages and dendritic cells induces a regulatory/tolerogenic phenotype and subverts theinnate and adaptive immune response to the tumor. During cancer therapies, PAFR-ligands can be generated, further aggravatingthe immune suppression. Moreover, some tumor cells express PAFR and its activation by PAFR-ligands generatedduring chemotherapy induce anti-apoptotic factors, which protect the tumor cells from death induced by these treatments.It is proposed that PAFR antagonists, administered in combination with chemotherapy, may represent a promisingstrategy for cancer treatment.

Na+/K+ ATPase Inhibitors in Cancer by Konstantinos Alevizopoulos, Theodora Calogeropoulou, Florian Lang, Christos Stournaras (988-1000).
Sodium potassium pump (Na+/K+ ATPase) is a transmembrane protein complex found in all higher eukaryotesacting as a key energy-consuming pump maintaining ionic and osmotic balance in cells. Recently recognized as an importanttransducer and/or integrator of various signals as well as a protein-protein interaction scaffold forming receptor complexeswith signaling properties, the most prominent pharmacological role of Na+/K+ ATPase inhibitors is the increase ofmyocardial contractility in pathologic conditions such as congestive heart failure. Consequently, modulators of Na+/K+ATPase such as digoxin have been approved by regulatory authorities and are widely used in the treatment of cardiac failuresince 1975. Initiating from early observations of reduction of cancer incidence in cardiac patients taking digoxin, recentepidemiological and other studies have consolidated the anti-cancer potential of Na+/K+ ATPase inhibitors in indicationssuch as prostate, breast, lung cancer or leukemia. More importantly, a new series of pharmacologically optimizedNa+/K+ ATPase inhibitors has recently shown strong anti-cancer activities in multiple preclinical assays and have reachedearly clinical trials. Altogether, these results suggest that Na+/K+ ATPase is an emerging cancer target that merits furtherinvestigation. In this review, we summarize key functional properties of the enzyme that are highly relevant for cancer cellselectivity, review the most prominent chemical classes of Na+/K+ ATPase inhibitors and analyze their downstream effectors.Moreover, we discuss overall development prospects of these candidate drugs on their way to becoming new effectivetreatments of cancer in patients.