Current Drug Targets (v.18, #4)

Meet Our Editorial Board Member by Mark J. Walker (375-375).

Cellular and Molecular Networks in Chronic Myeloid Leukemia: The Leukemic Stem, Progenitor and Stromal Cell Interplay by Danilo Perrotti, Giovannino Silvestri, Lorenzo Stramucci, Justine Yu, Rossana Trotta (377-388).
The use of imatinib, second and third generation ABL tyrosine kinase inhibitors (TKI) (i.e. dasatinib, nilotinib, bosutinib and ponatinib) made CML a clinically manageable and, in a small percentage of cases, a cured disease. TKI therapy also turned CML blastic transformation into a rare event; however, disease progression still occurs in those patients who are refractory, not compliant with TKI therapy or develop resistance to multiple TKIs. In the past few years, it became clear that the BCRABL1 oncogene does not operate alone to drive disease emergence, maintenance and progression. Indeed, it seems that bone marrow (BM) microenvironment-generated signals and cell autonomous BCRABL1 kinase-independent genetic and epigenetic alterations all contribute to: i. persistence of a quiescent leukemic stem cell (LSC) reservoir, ii. innate or acquired resistance to TKIs, and iii. progression into the fatal blast crisis stage. Herein, we review the intricate leukemic network in which aberrant, but finely tuned, survival, mitogenic and self-renewal signals are generated by leukemic progenitors, stromal cells, immune cells and metabolic microenvironmental conditions (e.g. hypoxia) to promote LSC maintenance and blastic transformation.

Unleashing the Guardian: The Targetable BCR-ABL/HAUSP/PML/PTEN Network in Chronic Myeloid Leukemia by Alessandro Morotti, Davide Torti, Giovanna Carra, Cristina Panuzzo, Sabrina Crivellaro, Riccardo Taulli, Carmen Fava, Angelo Guerrasio, Giuseppe Saglio (389-395).
The complete eradication of Chronic Myeloid Leukemia is still challenging even in the era of highly selective and potent BCR-ABL tyrosine kinase inhibitors (TKIs). The 'Achilles heel' of TKI-based CML therapy is the inability of TKI to effectively target CML stem cells. Several pathways have been described to induce TKI insensitiveness in quiescent CML stem cells. In this review, we will describe the BCR-ABL/HAUSP/PML/PTEN network, whose signaling mediators converge to regulate the function of the tumor suppressor PTEN. We will also highlight the pharmacological strategies to modulate PTEN functions in order to sustain CML stem cell eradication.

Is Going for Cure in CML Targeting Aberrant Glycogen Synthase Kinase 3β? by Concetta Saponaro, Michele Maffia, Nicola Di Renzo, Addolorata Maria Luce Coluccia (396-404).
Chronic Myelogenous Leukemia (CML)-initiating cells (CICs) express the hybrid oncoprotein BCR-ABL at the highest levels compared to their differentiated progeny but fail to expand at the same rate as downstream leukemic myeloid cells. Moreover, the primitive stem cell clone that originates the indolent CML chronic phase (CP) remains almost invariant as the disease evolves to a fatal blast crisis (BC). Compared to their healthy counterpart, the most dormant BCR-ABL+ CICs show the tendency to remain in a somewhat unusual 'proliferative quiescence', i.e. a prolonged low-energy viable state that restrains the frequency of symmetrical (self-renewing) cell divisions while enforcing cell cycle entry and myeloid commitment under cytokine support. Over the past few years, we and others have proposed the nutrient-sensing protein serine/threonine kinase GSK3β (glycogen synthase kinase 3β) as an attractive target to eradicate leukemia-initiating cells while sparing normal haematopoiesis. Beyond its natural negative effects on self-renewal, through the inhibitory phosphorylation of β-Catenin (Wnt signalling) and c-MYC (Hedgehog signalling), hyperactive GSK3β is reportedly crucial to link energy metabolism and nutrient availability to stem cell homeostasis processes. This review will integrate current evidence pertaining to the biological relevance of GSK3β in normal and malignant haematopoiesis, with particular emphasis on its role(s) at the CML CP stage and BC transformation. Preclinical evidence earmarking the use of novel small-molecule inhibitors of GSK3β as promsing anti-leukemia agents are also discussed.

Stem Cell Guardians - Old and New Perspectives in LSC Biology by Gillian A. Horne, Lorna Jackson, Vignir Helgason, Tessa L. Holyoake (405-413).
The introduction of tyrosine kinase inhibitors in chronic myeloid leukaemia (CML) has revolutionised disease outcome. However, despite this, progression to blast phase disease is high in those that do not achieve complete cytogenetic and major molecular response on standard therapy. As well as BCR-ABL-dependent mechanisms, disease persistence has been shown to play a key role. Disease persistence suggests that, despite a targeted therapeutic approach, BCR-ABL-independent mechanisms are being exploited to sustain the survival of a small population of cells termed leukaemic stem cells (LSCs). Increasing evidence highlights the importance of self-renewal and survival pathways in this process. This review will focus on the role of stem-cell restricted self-renewal pathways, namely Hedgehog, Notch, and Bone Morphogenic Pathway (BMP). Wingless-Int/?-Catenin (Wnt/?-Catenin) signalling will be discussed within a further review in this series in view of its regulatory role in GSK3?. Further to this, we will highlight the role of key transcriptional regulators, namely p53 and c- MYC, in targeting wider deregulated networks.

Pseudomonas aeruginosa is the most common Gram-negative bacterium associated with nosocomial and life-threatening chronic infections in cystic fibrosis patients. This pathogen is wellknown for its ability to attach to surfaces of indwelling medical devices to form biofilms, which consist of a regular array of extracellular polymers. Tenaciously bound to the surface of devices and inherently resilient to antibiotic treatment, P. aeruginosa poses a serious threat in clinical medicine and contributes to the persistence of chronic infections. Studies on microbial biofilms in the past decade involved mainly the understanding of environment signals, genetic elements and molecular mechanisms in biofilm formation, tolerance and dispersal. The knowledge obtained from the studies of these mechanisms is crucial in the establishment of strategies to eradicate or to prevent biofilm formation. Currently, biofilm infections are usually treated with combinations of antibiotics and surgical removal, in addition to frequent replacement of the infected device. More recently, specific natural sources have been identified as antibiofilm agents against this pathogen. This review will highlight the recent progress made by plant-derived compounds against P. aeruginosa biofilm infections in both in vitro or in vivo models.

Specific Targeting of Akt Kinase Isoforms: Taking the Precise Path for Prevention and Treatment of Cancer by Nand Kishor Roy, Devivasha Bordoloi, Javadi Monisha, Ganesan Padmavathi, Jibon Kotoky, Ramesh Golla, Ajaikumar B. Kunnumakkara (421-435).
Akt kinase is a serine threonine kinase that exists in three isoforms, located in different chromosomes and has distinct sites of expression which orchestrates diverse cellular processes required for normal functioning of the cell. Though, these Akt isoforms have some overlapping actions, but they also have specific roles and interestingly, sometimes they even perform contrasting functions. There are various alterations such as amplification, overexpression, mutation, etc. associated with these isoforms which have great implications in the development of cancer. Moreover, these alterations also induce chemo and radio resistance in cancer cells that impede the existing treatment modules. Furthermore, many reports have shown their potential as efficient prognostic biomarkers. Although, many studies have discussed the implications of Akt kinase proteins in different cancers but in-depth analysis of isoform- specific involvement is least examined and hence demands more attention. This review discusses the divergent roles of Akt isoforms comprehensively in different cancers and finding their immense prospects as potential targets for cancer prevention and treatment.

Patients who underwent solid organ transplantation frequently suffer from different skin diseases, as consequence of the immunosuppressive treatment. Specific cutaneous side effects such as acne, hypertricosis or other pilosebaceous unit disorders, gingival hyperplasia, purpura or teleangiectasies are commonly associated to immunosuppressive medications. The majority of these conditions are benign, but the aesthetic concern may affect the patient is quality of life and reduce the adherence to the therapy. Moreover, solid organ transplant recipients frequently develop skin infections, as an indirect consequence of the immunosuppressive regimens. Herpes virus reactivation is more common few months after transplantation, whereas when the immunosuppression is reduced, the skin infections are mainly represented by human papilloma virus infections and localized mycosis. Bacterial infections are relatively rare. Long-term consequences of the immunosuppressive therapy are represented by development of precancerosis and skin cancers, with a risk that enhances over the time and a significant impact on patient survival. The aim of this paper is to provide an overview of the data published in the recent literature about this topic, in order to characterize the main skin disorders associated to the use of immunosuppressive drugs in solid organ recipients, giving information about their risk, epidemiology, clinical manifestations and management.

The Hippo Pathway as Drug Targets in Cancer Therapy and Regenerative Medicine by Shunta Nagashima, Yijun Bao, Yutaka Hata (447-454).
Yes-associated protein 1 (YAP1) and transcriptional co-activator with PDZ-binding motif (TAZ) co-operate with numerous transcription factors to regulate gene transcriptions. YAP1 and TAZ are negatively regulated by the tumor suppressive Hippo pathway. In human cancers, the Hippo pathway is frequently deregulated and YAP1 and TAZ escape the inhibition by the Hippo pathway. The upregulation of YAP1 and TAZ induces epithelial-mesenchymal transition and increases drug resistance in cancer cells. TAZ is implicated in cancer stemness. In consequence cancers with hyperactive YAP1 and TAZ are associated with poor clinical prognosis. Inhibitors of YAP1 and TAZ are reasoned to be beneficial in cancer therapy. On the other hand, since YAP1 and TAZ play important roles in the regulation of various tissue stem cells and in tissue repair, activators of YAP1 and TAZ are useful in the regenerative medicine. We discuss the potential application of inhibitors and activators of YAP1 and TAZ in human diseases and review the progress of drug screenings to search for them.

ROCK in CNS: Different Roles of Isoforms and Therapeutic Target for Neurodegenerative Disorders by Cheong-Meng Chong, Nana Ai, Simon Ming-Yuen Lee (455-462).
Rho-associated protein kinase (ROCK) is a serine-threonine kinase originally identified as a crucial regulator of actin cytoskeleton. Recent studies have defined new functions of ROCK as a critical component of diverse signaling pathways in neurons. In addition, inhibition of ROCK causes several biological events such as increase of neurite outgrowth, axonal regeneration, and activation of prosurvival Akt. Thus, it has attracted scientist's strong attentions and considered ROCK as a promising therapeutic target for the treatment of neurodegenerative disorders including Alzheimer disease, Parkinson's disease, Huntington's disease, multiple sclerosis, and amyotrophic lateral sclerosis. However, ROCK has two highly homologous isoforms, ROCK1 and ROCK2. Accumulated evidences indicate that ROCK1 and ROCK2 might involve in distinct cellular functions in central nervous system (CNS) and neurodegenerative processes. This review summarizes recent updates regarding ROCK isoformspecific functions in CNS and the progress of ROCK inhibitors in preclinical studies for neurodegenerative diseases.

MicroRNAs as Candidate Drug Targets for Cardiovascular Diseases by Pengzhou Hang, Jing Guo, Chuan Sun, Zhimin Du (463-472).
MicroRNAs (miRNAs) are small conserved noncoding RNAs which function as posttranscriptional regulators of gene expression. Studies over the last 20 years have revealed the essential functions of miRNAs in regulating cardiovascular biology (such as cardiovascular cell differentiation, growth, proliferation and apoptosis) and crucial roles in controlling cardiovascular disease (CVD), indicating the potential of these small molecules as therapeutic targets and/or agents for CVD. Moreover, miRNAs in the circulation or other body fluids are stable and readily detectable, and more importantly often disease-associated, which makes them promising novel biomarkers for diagnosis and prognosis of CVDs. Furthermore, emerging evidence uncovered miRNAs as new targets and/or regulators of cardiovascular medications given the ability of miRNAs to interact with some cardiovascular drugs, which opens up new opportunities for the research and development of novel CVD drugs. Herein, we summarize current knowledge regarding the potential applications of miRNAs in the therapy of CVD, including myocardial ischemia, cardiac hypertrophy/heart failure, interstitial fibrosis, arrhythmia, diabetes and hypertension and discuss the therapeutic potential and challenge of miRNAs in drug discovery.

Sirtuins: Possible Clinical Implications in Cardio and Cerebrovascular Diseases by Valeria Conti, Maurizio Forte, Graziamaria Corbi, Giusy Russomanno, Luigi Formisano, Alessandro Landolfi, Viviana Izzo, Amelia Filippelli, Carmine Vecchione, Albino Carrizzo (473-484).
Mammalian sirtuins (SIRT1-7) are NAD+-dependent deacetylases, which play an important role in aging and in a wide range of cellular functions. SIRT1, the best-characterized member of the family, acts as a sensor of the redox state and triggers in the cell the appropriate defense response. A large body of evidence has showed that SIRT1 induces both cellular and systemic protective effects in the cardiovascular system by preventing stress-induced apoptosis and senescence, and mitigating endothelial dysfunction. Hence, SIRT1 is now foreseen as a potential therapeutic target for a growing number of cardiovascular diseases. Recently, it has been suggested that SIRT1 activation could also be considered as a neuroprotective strategy. Indeed, SIRT1 protects against ischemia/reperfusion injury both in vitro and in vivo and avoids severe ischemic damage by preserving cerebral blood flow. In the last years it was suggested that others sirtuins, in particular SIRT3 and SIRT6, could exert beneficial effects in vascular syndromes. The aim of this review was to describe and discuss recent experimental evidence on the effects of SIRT1 and other sirtuins on the pathophysiology of cardio- and cerebrovascular diseases, underlying a potential therapeutic effect of these enzymes in the treatment and/or prevention of such conditions.

The Role of Gender-specific Cytokine Pathways as Drug Targets and Gender- specific Biomarkers in Personalized Cancer Therapy by Anna Maria Berghella, Ida Contasta, Roberto Lattanzio, Giancarlo Di Gregorio, Irma Campitelli, Marino Silvino, Luigi Liborio Liberatore, Luca Navarra, Giampaolo Caterino, Antonio Mongelli, Vincenzo Vittorini, Matteo Basta, Mauro Domenicucci, Nunzia Antonucci, Tiziana Del Beato, Enzo Secinaro, Fabiana Ciccone, Patrizia Pellegrini (485-495).
The definition of personalized treatments in tumor disease could lead to an improvement of the therapeutic success rate. Therefore, biomarkers are urgently required in order to select the patients that could benefit from adjuvant therapies in the initial phase of the disease and to better define and treat the clinical/therapeutic subgroups in the advanced pathological phases. Disregulation of cytokine physiological network is directly involved in the genesis and progression of tumors. Cytokines are of central importance in the regulation of immune system, but they are rarely released singly: each cytokine is able to induce the production of many other factors leading to a network in which they cooperate with other cell regulators such as hormones and neuropeptides. For these reasons the research must be directed to the evaluation of the interrelationships between the different cytokines and their respective pathways, as well as their contribution to the disease aetiology and progression in order to identify real and effective drug targets and biomarkers. The T CD4+ helper cells (Th) have various subpopulations, among which Th1, Th2, Th3, Th9 and Th17, respectively produce cytokines. It has become clear that disorders within the interactions of the network of these cytokines can produce neoplastic diseases. Furthermore, studies focusing on gender have shown that the homeostasis of the immune system is controlled by pathways of cytokines that are different between sexes and defined for this reason “genderspecifics”. Therefore, this perspective article aims to highlight the significance of these cytokine pathways in order to identify new clinical strategies and personalized therapy in neoplastic diseases.