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Crosstalk Signalling Role in Modulation of Drugs Side Effects
Susanna P. Garamszegi and Nandor Garamszegi
[Abstract] [FULL-TEXT INQUIRY] [PMID: 21554210 PubMed - indexed for MEDLINE] [BSP/CMP/E-Pub/00006]


Parkinson’s Disease: A Role for the Immune System
Dwight C. German, Todd Eagar and Patricia K. Sonsalla
[Abstract] [FULL-TEXT INQUIRY] [PMID: 21675953 PubMed - indexed for MEDLINE] [BSP/CMP/E-Pub/00007]


GRK2 and Beta-Arrestins in Cardiovascular Disease: Established and Emerging Possibilities for Therapeutic Targeting
Alicia N. Harvey, Kristy Nguyen and Anastasios Lymperopoulos
[Abstract] [FULL-TEXT INQUIRY] [PMID: 21756224 PubMed - indexed for MEDLINE] [BSP/CMP/E-Pub/00008]


Hot Topic Issue: Molecular and Pharmacological Aspects of Existing and Experimental Bone Anabolic Therapies


Editorial:
Naibedya Chattopadhyay
[BSP/CMP/E-Pub/00009]


Anabolic effects of intermittent PTH on osteoblasts
Edward M. Greenfield
[Abstract] [Purchase Article] [BSP/CMP/E-Pub/00010]


Insulin Like Growth Factor-I: A Critical Mediator Of The Skeletal Response To Parathyroid Hormone
Daniel D Bikle and Yongmei Wang
[Abstract] [FULL-TEXT INQUIRY] [BSP/CMP/E-Pub/00011]


Insulin-like growth factor-I molecular pathways in osteoblasts: Potential targets for pharmacological manipulation
Kristen E. Govoni
[Abstract] [FULL-TEXT INQUIRY] [BSP/CMP/E-Pub/00012]


The role of BMPs in bone anabolism and their potential targets SOST and DKK1
Nobuhiro Kamiya
[Abstract] [Purchase Article] [BSP/CMP/E-Pub/00013]


Potential of modulating Wnt signaling pathway toward the development of bone anabolic agent
Ulf Krause and Carl A. Gregory
[Abstract] [Purchase Article] [BSP/CMP/E-Pub/00014]


Prostaglandin E2 receptors as potential bone anabolic targets – selective EP4 receptor agonists.
Joseph Pagkalos, Andreas Leonidou, Mohammed As-Sultany, Manolis Heliotis, Athanasios Mantalaris, Eleftherios Tsiridis
[Abstract] [FULL-TEXT INQUIRY] [BSP/CMP/E-Pub/00015]


Antagonizing the calcium-sensing receptor: towards new bone anabolics?
Daniela Riccardi
[Abstract] [FULL-TEXT INQUIRY] [BSP/CMP/E-Pub/00016]


Potential Anti-catabolic and Anabolic Properties of Strontium Ranelate
Romuald Mentaverri, Michel Brazier, Said Kamel, Patrice Fardellone
[Abstract] [FULL-TEXT INQUIRY] [BSP/CMP/E-Pub/00017]


Activin Receptor Signaling: A Potential Therapeutic Target for Osteoporosis
Sutada Lotinun, R. Scott Pearsall, William C. Horne, Roland Baron
[Abstract] [FULL-TEXT INQUIRY] [BSP/CMP/E-Pub/00018]


Naturally plant-derived compounds: role in bone anabolism
Marie-Noëlle Horcajada and Elizabeth Offord
[Abstract] [FULL-TEXT INQUIRY] [BSP/CMP/E-Pub/00019]


Editorial: PPAR Ligands and Cardiovascular Disorders: Friend or Foe
Pitchai Balakumar and Gowraganahalli Jagadeesh
[BSP/CMP/E-Pub/00020]


The involvement of PPARs in the causes, consequences and mechanisms for correction of cardiac lipotoxicity and oxidative stress
M.C. Sugden, M.P. Warlow and M.J. Holness
[Abstract] [FULL-TEXT INQUIRY] [BSP/CMP/E-Pub/00021]


Healing the Diabetic Heart: Modulation of Cardiometabolic Syndrome through Peroxisome Proliferator Activated Receptors (PPARs)
Tom Hsun-Wei Huang and Basil D Roufogalis
[Abstract] [FULL-TEXT INQUIRY] [BSP/CMP/E-Pub/00022]


Effects of PPARγ agonists against vascular and renal dysfunction
Akira Sugawara, Akira Uruno, Ken Matsuda, Tadao Funato, Akiko Saito-Hakoda, Masataka Kudo and Sadayoshi Ito
[Abstract] [FULL-TEXT INQUIRY] [BSP/CMP/E-Pub/00023]


Use of clinically available PPAR agonists for heart failure; do the risks outweigh the potential benefits?
Satyam Sarma
[Abstract] [FULL-TEXT INQUIRY] [BSP/CMP/E-Pub/00024]


Assessment of cardiac safety for PPARγ agonists in rodent models of heart failure: A translational medicine perspective
Xinkang Wang
[Abstract] [FULL-TEXT INQUIRY] [BSP/CMP/E-Pub/00025]


Peroxisome Proliferator-Activated Receptor-γ (Ppar-γ) Agonists On Glycemic Control, Lipid Profile And Cardiovascular Risk
Giuseppe Derosa and Pamela Maffioli
[Abstract] [FULL-TEXT INQUIRY] [BSP/CMP/E-Pub/00026]


Effects of PPARγ ligands on vascular tone
Salvatore Salomone and Filippo Drago
[Abstract] [FULL-TEXT INQUIRY] [BSP/CMP/E-Pub/00027]


PPARγagonists in polycystic kidney disease with frequent development of cardiovascular disorders
Shizuko Nagao and Tamio Yamaguchi
[Abstract] [FULL-TEXT INQUIRY] [BSP/CMP/E-Pub/00028]


The application of mass spectrometry to proteomics and metabolomics in biomarker discovery and drug development
Toshiyuki Mikami, Mikio Aoki and Toru Kimura
[Abstract] [FULL-TEXT INQUIRY] [BSP/CMP/E-Pub/00029]


Hot Topic Issue: Evolving drug targets in DNA base excision repair for cancer therapy


Editorial:
Dr. Srinivasan Madhusudan
[BSP/CMP/E-Pub/00030]


Overview of Base Excision Repair Biochemistry
Yun-Jeong Kim and David M. Wilson III
[Abstract] [FULL-TEXT INQUIRY] [BSP/CMP/E-Pub/00031]


Small-Molecule Inhibitors of APE1 DNA Repair Function: An Overview
Rasha I. Al-Safi,  Srinivas Odde,  Yumna Shabaik and Nouri Neamati
[Abstract] [FULL-TEXT INQUIRY] [BSP/CMP/E-Pub/00032]


APE1/Ref-1Role in Redox Signaling: Translational Applications of Targeting the Redox Function of the DNA Repair/Redox Protein APE1/Ref-1
Mark R. Kelley, Millie M. Georgiadis and Melissa L. Fishel
[Abstract] [FULL-TEXT INQUIRY] [BSP/CMP/E-Pub/00033]


Biological Relevance of DNA Polymerase Beta and Translesion Synthesis Polymerases to Cancer and its Treatment
Nils H. Nicolay, Thomas Helleday and Ricky A. Sharma
[Abstract] [FULL-TEXT INQUIRY] [BSP/CMP/E-Pub/00034]


Targeting DNA Polymerase β for therapeutic intervention
Eva M. Goellner, David Svilar, Karen H. Almeida and Robert W. Sobol
[Abstract] [FULL-TEXT INQUIRY] [BSP/CMP/E-Pub/00035]


Base excision repair, the redox environment and therapeutic implications
Sarah J. Storr, Caroline M. Woolston and Stewart G. Martin
[Abstract] [FULL-TEXT INQUIRY] [BSP/CMP/E-Pub/00036]


Temozolomide: Mechanisms of Action, Repair and Resistance
Jihong Zhang, Malcolm FG Stevens and Tracey D Bradshaw
[Abstract] [FULL-TEXT INQUIRY] [BSP/CMP/E-Pub/00037]


Base Excision Repair Factors Are Promising Prognostic And Predictive Markers In Cancer
Lucy Gossage, Christina Perry, Rachel Abbotts and Srinivasan Madhusudan
[Abstract] [FULL-TEXT INQUIRY] [BSP/CMP/E-Pub/00038]



Abstracts


Crosstalk Signalling Role in Modulation of Drugs Side Effects
Susanna P. Garamszegi and Nandor Garamszegi
[FULL-TEXT INQUIRY] [PMID: 21554210 PubMed - indexed for MEDLINE] [BSP/CMP/E-Pub/00006]

Tumorigenesis is regulated by the complex cell-matrix signalling interactions that incorporate feedback mechanisms from constantly evolving microenvironments. Under normal circumstances, these matrix signalling processes together with infiltrating immune cells tightly control the extent of tissue remodelling. They are the key elements of regulated homeostatic repair of local matrix architecture and biological function. In contrast, the pathological tumorigenesis employing similar mechanisms and cellular components to change cellular phenotype promoting proliferation and transformation. However, there is a significant knowledge gap in our understanding about the network integration of different matrix induced signalling processes and their connection to drug side effects.

Using epithelial tumorigenesis as a model system, we show that drug actions and pathological conditions are associated with crosstalk signalling mechanisms. These processes functionally integrate microenvironmental cues and generate representative gene expression profiles that are different from those generated by the native ligand-driven signalling mechanisms. Particularly in this review, we are focusing on crosstalk signalling processes that  are sensitive to transforming growth factor receptor type I (TβRI) inhibitor A83-01 (3-(6-Methyl-2-pyridinyl)-N-phenyl-4-(4-quinolinyl)-1H-pyrazole-1-carbothioamide).  This process is affecting inflammatory gene expression, epithelial to mesenchymal transition, migration, proliferation, and changes in metastatic gene expressional patterns. As a result, phenotypic and functional modifications to cells and their immediate microenvironments are unavoidable.

Here we demonstrate that future screening strategies for unintended drug side effects from molecular to systemic levels would benefit from future crosstalk signalling analysis. Thorough analysis could be used to forecast the diverse and highly variable gene expression patterns caused by pathological microenvironmental conditions which become apparent only in larger patient populations.
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Parkinson’s Disease: A Role for the Immune System
Dwight C. German, Todd Eagar and Patricia K. Sonsalla
[FULL-TEXT INQUIRY] [PMID: 21675953 PubMed - indexed for MEDLINE] [BSP/CMP/E-Pub/00007]

Parkinson’s disease (PD) is a progressive neurodegenerative disorder associated with the loss of catecholaminergic neurons in several brain regions.  The motor symptoms of the disease are related to degeneration of the midbrain dopaminergic neurons, which occurs some time after the disease has begun. Both the innate and adaptive immune systems appear to play a role in the neurodegenerative process, and may contribute to disease progression. Here we review the neuropathology of PD with attention focused on the involvement of the innate immune cells (microglia) and the adaptive immune cells (T lymphocytes). In addition, we discuss animal models of the disease with emphasis on a progressive rat model which allows a detailed analysis of how the immune system contributes to neurodegeneration both during early and late stages of degeneration. Finally, for the early detection and treatment of PD, we discuss immunotherapy approaches.
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GRK2 and Beta-Arrestins in Cardiovascular Disease: Established and Emerging Possibilities for Therapeutic Targeting
Alicia N. Harvey, Kristy Nguyen and Anastasios Lymperopoulos
[FULL-TEXT INQUIRY] [PMID: 21756224 PubMed - indexed for MEDLINE] [BSP/CMP/E-Pub/00008]

Heptahelical G protein-coupled receptors, such as the β-adrenergic and the angiotensin II type 1 receptors, are the most diverse and therapeutically important family of receptors in the human genome, playing major roles in the physiology of various organs/tissues including the heart and blood vessels. Ligand binding activates heterotrimeric G proteins that transmit intracellular signals by regulating effector enzymes or ion channels. G protein signaling is terminated, in large part, by phosphorylation of the agonist-bound receptor by the family of G-protein coupled receptor kinases (GRKs), with GRK2 being its most prominent member, followed by βarrestin binding, which uncouples the phosphorylated receptor and G protein and subsequently targets the receptor for internalization. As the receptor-βarrestin complex enters the cell, βarrestins serve as ligand-regulated scaffolds that recruit a host of intracellular proteins and signal transducers, thus promoting their own wave of signal transduction independently of G-proteins. A large number of preclinical studies in small and large animals over the past several years have pinpointed specific pathophysiologic roles played by these two families of receptor-regulating proteins in various cardiovascular diseases, directly implicating them in disease pathology and suggesting them as potential therapeutic targets. The present review gives an account of what is currently known about the benefits of cardiac and adrenal GRK2 inhibition for cardiovascular disease treatment, and also discusses the exciting new therapeutic possibilities emerging from uncovering the physiological roles of βarrestin-mediated signaling in vivo in the cardiovascular system.
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Editorial:
Naibedya Chattopadhyay
[BSP/CMP/E-Pub/00009]

Osteoporosis is the most prevalent form of metabolic bone disease and represents an implacable epidemic growing rapidly among the ageing population world over. As per International Osteoporosis Foundation census, more than 200 million people in the world suffer from osteoporosis, of which about 80% are women. Antiresorptive and bone-forming drugs are the two main options available for the treatment of osteoporosis. Most of the antiresorptive therapies uncouples the bone remodeling cycle (bone resorption followed by formation) resulting in an initial increase in bone mass due to inhibition of osteoclastic resorption while osteoblasts continue to fill in the resorbed space. However, this process does not last beyond two years after which osteoblast function declines. Hence, bone anabolic therapy (stimulating the function of bone forming osteoblasts) is necessary to replace lost bone or rebuild new bone mass.

Intermittent parathyroid hormone (iPTH) is capable of increasing bone mineral density, restoring skeletal microarchitecture, and curtailing fracture risk to a greater extent than the antiresorptive therapies. However, iPTH therapy has the following limitations: i) it carries a black-box warning because it is associated with an increased risk of osteosarcoma in rats, ii) daily injection is cumbersome and may negatively influence adherence to treatment and iii) it is recommended only once in a lifetime for a maximum of two years. Hence, there is a tremendous need for new osteogenic drugs and other preparations of PTH to provide a better option and create a competitive environment.

In this highly topical issue, an attempt was made by bringing together researchers from different areas of osteoblast biology for a comprehensive review of the recent advances in bone anabolic research drawn from the studies of basic bone biology as well as those involving experimental therapeutics of emerging osteogenic or anticatabolic agents/compounds. Because the bone anabolic effect of iPTH was discovered out of serendipity, understanding its mode of action in osteoblasts became important. As osteoporosis therapy is likely to be long-term, the safety of any putative osteogenic agent merits careful consideration. Target-based drug development, founded on solid mechanistic understanding should yield molecules with better safety profiles. Therefore, a great deal of emphasis is placed on various putative osteogenic candidate molecules and understanding of their mechanisms of action and the context in which these candidates may become therapeutic targets. Accordingly, it is expected that this theme issue will invite attention of both basic (biochemists and pharmacologists) and clinical (endocrinologists and orthopedists) researchers.

The issue begins with a review of studies elucidating the mechanism by which iPTH functions. Edward M. Greenfield from Case Western Reserve University, USA, has made an insightful discussion of the complex cellular and molecular mechanisms underlying the paradox that iPTH increases bone mass, while a continuous administration induces bone loss. Subsequently, Daniel Bikle and Yongmei Wang from University of California at San Francisco, USA, review the interaction between PTH and insulin-like growth factor – I (IGF-I) learned from the studies of various mouse models that have either global deletion of IGF-I or bone cell-specific (osteoblast, osteoprogenitor or osteoclast) deletion of IGF-I receptor (IGF-IR). Their review helps to delineate the anabolic and catabolic effect of PTH in bone wherein IGF-1/IGF-IR system acts as a crucial mediator.

Although our understanding of the PTH action on bone anabolism mediated by IGF-I, thanks to the contribution from Bikle’s group, has been recent, the anabolic effect of systemic IGF-I has been recognized for a long time. Kristen Govoni from the University of Connecticut, USA, summarizes various gene manipulation studies in mouse models that have confirmed an essential role of IGF-I and its signaling pathways in skeletal biology. The observations are that overexpression of IGF-I increase the volume of cancellous bone by increasing bone formation and targeted deletion of the IGF-IR or deletions of the insulin–IGF-I signaling molecules [insulin-receptor substrate -1 and 2] cause osteopenia due to impaired bone formation. Six IGF-binding proteins (IGFBP 1-6) can form a complex with IGF-I and modulate the levels of free IGF in plasma and peripheral tissues. IGFBP-3 and -5 are known stimulators of IGF-I actions, whereas IGFBP-1, -2, -4 and -6 are inhibitors of IGF-I action in bone. Govoni also describes the role of key IGFBPs in regulating IGF-I action in bone by reviewing data from knock out/transgenic mice models. This review allows assessment of potential molecular targets in the scheme of IGF-1-IGFBPs-IGF receptor signaling pathway.

While IGF-I enhances the function of mature osteoblasts, bone morphogenetic proteins (BMP) and wingless type (Wnt) proteins induce the differentiation of mesenchymal cells toward osteoblasts. Out of some 15 BMPs known to date, BMP-2, and 7 are of particular interest given their specific orthopedic application approved by U.S. Food and Drug Administration in areas such as spinal fusion and long bone non-union fracture. Although BMPs are bone anabolic agents, Nobuhiro Kamiya from Texas Scottish Rite Hospital for Children, USA, discusses the role of BMPs in bone remodeling. BMPs have both bone anabolic and catabolic effects. BMPs favor the increase in bone mass by impacting chondrocytes and mesenchymal cells while reducing bone mass via its action on osteoblasts. Dr. Kamiya also discusses the potential relationship between BMP and Wnt signaling in osteoblasts, which appear to regulate each other. Furthermore, he provides the basis for molecular events/targets in BMP signaling that can serve as potential for therapeutic intervention.

Ulf Krause and Carl Gregory from Texas A and M Health Science Center, USA, discussed canonical and non-canonical Wnt signaling in osteoblasts from studies that include biochemical, transgenic mouse and human disease models. Their review provides a strong rationale for glycogen synthetase kinase 3 beta (GSK3β) and peroxisome proliferator-activated receptor gamma (PPARγ) as potential targets for osteoinductive therapy. Small molecule as well as antibody-based approaches targeting several nodal points of the tightly regulated Wnt pathway has also been discussed.

Prostaglandin E2 (PGE2) stimulates both bone resorption and bone formation but more in favor of the latter, thus increasing bone mass and bone strength. Pagkalos et al from Imperial College London, UK, discuss a potential option of selective PGE2 agonist as a bone anabolic agent. Their review is mainly focused on EP4 subtype of PGE2 receptor as this subtype is expressed in human bone and animal studies show that the anabolic effect of PGE2 is mediated by this receptor. The authors discuss reports showing reversal of osteoporotic changes, enhanced strength of bone-implant interface and synergistic effect on the BMP-2-mediated osteoinduction by EP4 agonists. Although promising for bone anabolic therapy, selective EP4 receptor agonists require elucidation of their safety profile to proceed towards clinical applications.

One way to circumvent the problems associated with iPTH therapy is to elicit PTH secretion from the parathyroid gland by antagonizing the function of parathyroid calcium-sensing receptor (CaSR). Daniela Riccardi from Cardiff University, UK, reviews the attempts made to mirror the cyclical pattern of injectable and endogenous PTH by orally active calcilytics (small molecule antagonists of CaSR) to promote new bone formation. Riccardi’s review covers various classes of calcilytics that have undergone clinical trials in osteoporotic patients and critical assessment of the potential of calcilytic in replacing iPTH therapy.

Strontium is a trace element that has been shown to uncouple bone remodeling by increasing bone formation and decreasing bone resorption, for which it is ascribed as a dual action or mixed agent. Strontium Ranelate (SrR) is now in clinical use for reducing the risk of vertebral and non-vertebral fracture. Although the mechanism of action is still not well understood, Mentaverri et al from Amiens University Hospital, France, reviewed the signaling of SrR via CaSR in osteoblasts and osteoclasts. In addition, the results of various clinical trials conducted to assess anti-osteoporotic efficacy of SrR are also discussed. Another example of dual anabolic-antiresorptive agent is a soluble activin receptor IIA fusion protein (ActRIIA-Fc) that neutralizes activin and increases bone mass and strength with no changes in muscle mass. Lotinun et al from Harvard School of Dental Medicine, USA, made a comprehensive review on the role of activin receptor signaling in bone turnover and preclinical studies on ActRIIA-Fc that have shown promise for osteoporosis and cancer-related osteolytic diseases.

Increasing evidence indicate that naturally occurring polyphenolic compounds favorably modulate bone metabolism. Bone sparing action of polyphenolic compounds is thought to be mediated by anti-oxidant properties that attenuate the production of oxidation-derived free radicals from the bone resorbing osteoclasts and their precursors. In addition, many polyphenolic compounds act like naturally occurring selective estrogen receptor modulators. Marie-Noëlle Horcajada and Elizabeth Offord from Nestlé Research Center, Switzerland, review the possible bone anabolic effects of various extracts and their bioactive compounds derived from dietary sources and medicinal plants. Overall assessment of their mode of action suggests that these naturally occurring agents function in mixed/dual action mode, inhibiting bone resorption and stimulating bone formation.

In summary, this issue provides a comprehensive overview of several lines of intense research being carried out in the field of bone anabolic agents. Hopefully, in the next several years, this basic understanding of recently identified bone anabolic targets and the mechanism of actions of already used therapy will lead to the emergence of new and improved bone anabolic agents. I would like to thank each author of this special issue for a wonderful contribution. 
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Anabolic effects of intermittent PTH on osteoblasts
Edward M. Greenfield
[Purchase Article] [BSP/CMP/E-Pub/00010]

Intermittent parathyroid hormone (iPTH) is the only FDA-approved therapy for bone loss due to conditions such as osteoporosis that increases bone formation by osteoblasts; all other therapies approved for osteoporosis block bone resorption by osteoclasts. The anabolic effects of iPTH are likely due to a combination of multiple mechanisms, including induction of immediate-early genes, increased expression and/or activity of essential osteoblast transcription factors, and downregulation of anti-osteogenic proteins, such as sclerostin. In contrast, continuous administration of PTH induces bone loss primarily due to up-regulation of RANKL expression and inhibition of osteoprotegerin expression.
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Insulin Like Growth Factor-I: A Critical Mediator Of The Skeletal Response To Parathyroid Hormone
Daniel D Bikle and Yongmei Wang
[FULL-TEXT INQUIRY] [BSP/CMP/E-Pub/00011]

This review focuses on the mechanisms by which PTH stimulates both osteoblast and osteoclast function, emphasizing the critical role that IGF-I plays in these processes. After reviewing the current literature on the skeletal actions of PTH and the modulation of IGF action on bone by the different IGF-binding proteins,  the review then examines studies from mouse models in which IGF-I or its receptor have been selectively deleted in different cells of the skeletal system, in particular osteoprogenitors, mature osteoblasts, and osteoclasts.  Mice in which IGF-I production has been deleted from all cells are deficient in both bone formation and bone resorption with few osteoblasts or osteoclasts in bone in vivo, reduced osteoblast colony forming units, and an inability of either the osteoblasts or osteoclast precursors to support osteoclastogenesis in vitro.  Mice in which the IGF-I receptor is specifically deleted in mature osteoblasts have a mineralization defect in vivo, and bone marrow stromal cells from these mice fail to mineralize in vitro. Mice in which the IGF-I receptor is deleted in osteoprogenitor cells have a marked reduction in osteoblast proliferation and differentiation leading to osteopenia. Finally mice lacking the IGF-I receptor in their osteoclasts have increased bone and decreased osteoclast formation. PTH fails to stimulate bone formation in the mice lacking IGF-I or its receptor in osteoblasts or enhance the signaling between osteoblasts and osteoclasts through RANKL/RANK and Ephrin B2/Eph B4, emphasizing the role IGF-I signaling plays in cell-communication per se and as stimulated by PTH.  
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Insulin-like growth factor-I molecular pathways in osteoblasts: Potential targets for pharmacological manipulation
Kristen E. Govoni
[FULL-TEXT INQUIRY] [BSP/CMP/E-Pub/00012]

The insulin-like growth factors (IGFs) are the most abundant growth factors stored in bone and produced by osteoblasts.  IGF-I is an important regulator of osteoblast function and required for optimal bone development and maintenance.  IGF-I can act in an endocrine, paracrine or autocrine manner and is regulated by a family of six IGF binding proteins (IGFBPs). The IGFBPs are often found bound to IGF-I in the circulation or complexed with IGF-I in osteoblasts.  IGFBP-3 and -5 are known stimulators of IGF-I actions, whereas IGFBP-1, -2, -4 and -6 are known inhibitors of IGF-I action in bone.  Once IGF-I binds to its receptor (type 1 IGF receptor) it initiates a complex signaling pathway including the phosphoinositol 3-kinase (PI3-K)/3-PI-dependent kinase (PDK)-1/Akt pathway and the Ras/Raf/mitogen-activated protein (MAP) kinase pathway which stimulate cell function and/or survival.  Based on the critical role for IGF-I in osteoblasts, it is a logical candidate for anabolic therapy.  However, systemic administration of IGF-I is not cell specific and a limited number of long term experiments have been completed to date.   Several recent findings indicate that many of the IGFBPs and specific proteins in the IGF-I signaling pathways are also potent anabolic factors in regulating osteoblast function.  This review will focus on the role of these factors in mediating IGF-I action in osteoblasts and how they may serve as potential targets to stimulate osteoblast function and bone formation.
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The role of BMPs in bone anabolism and their potential targets SOST and DKK1
Nobuhiro Kamiya
[Purchase Article] [BSP/CMP/E-Pub/00013]

Bone morphogenetic proteins (BMPs) were discovered in 1965 as potent inducers of ectopic bone formation when implanted subcutaneously. BMP2, BMP4, BMP6, and BMP7 are osteoinductive, and BMP2 and BMP7 are currently approved for clinical applications such as bone fracture healing and spine surgery. Although BMPs’ role in bone formation is well known, the current clinical data supporting their effectiveness are not robust, possibly in part because BMPs affect bone resorption as well.  BMPs can reduce bone mass by inducing osteoclastogenesis via the RANKL-OPG pathway, which is a critical regulator of osteoclasts by osteoblasts. BMPs have both bone anabolic and catabolic effects by affecting multiple cell types in bone such as mesenchymal cells, chondrocytes, osteoblasts, osteoclasts, and endothelial cells. We recently generated an osteoblast-targeted deletion of BMP signaling using a Cre-loxP strategy and found that BMP signaling in osteoblasts can inhibit Wnt signaling through the Wnt inhibitors DKK1 and SOST. Loss-of-function of either DKK1 or SOST, which are downstream targets of BMPs, causes a high bone mass phenotype in humans and mice, suggesting an importance of DKK1 and SOST for bone mass regulation. There are many bone anabolic effectors that control bone mass such as BMPs, PTH, and Wnt inhibitors. This article will focus on BMPs’ effects on bone anabolism and propose a potential network of the bone mass mediators BMPs, PTH, and SOST. We believe it is important to understand this network to guide the clinical application of bone anabolic agents.
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Potential of modulating Wnt signaling pathway toward the development of bone anabolic agent
Ulf Krause and Carl A. Gregory
[Purchase Article] [BSP/CMP/E-Pub/00014]

Normal bone homeostasis is the result of a cross-talk between the anabolic axis (osteoblast differentiation) and catabolic axis (osteoclast remodeling). A disruption of this tightly regulated relationship leads to imbalanced bone turnover which ultimately results in diseases of the skeleton. Given that the majority of disease states are characterized by an inadequate renewal of osteoblasts, and the canonical wingless (Wnt) pathway is critical for their differentiation from progenitors, this represents an intriguing target for bone therapy. This mini-review focuses on the different options available for pharmaceutical enhancement of osteogenic differentiation through targeting the various proteins involved in Wnt signaling.
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Prostaglandin E2 receptors as potential bone anabolic targets – selective EP4 receptor agonists.
Joseph Pagkalos, Andreas Leonidou, Mohammed As-Sultany, Manolis Heliotis, Athanasios Mantalaris, Eleftherios Tsiridis
[FULL-TEXT INQUIRY] [BSP/CMP/E-Pub/00015]

Prostaglandin E2 is known to be a potent metabolite in bone biology. Its effects are mediated via four receptor subtypes with different properties, effects and mechanisms of action. The EP2 and EP4 receptors have been extensively investigated as bone anabolic therapy targets in the literature. The aim of this review was to analyse the available evidence supporting the use of selective agonists for those receptors for anabolic bone application purposes. Although several studies report on the presence of the EP2 receptor in several cell types, efforts to directly confirm the presence of this receptor in human bone cells have not been successful. The EP4 receptor however has been identified in human bone cells and its significant role in bone biology has been demonstrated with the use of selective agonists, antagonists and transgenic small animals. The use of selective EP4 agonists reversed established osteoporotic changes, enhanced the bone-implant interface strength and was shown to have a synergistic effect when used with other bone cell targeting pharmacological agents such as BMP-2 and bisphosphonates. Further elucidation of the side-effect profile of prostanoid and non-prostanoid agonists is required for these agents to proceed towards clinical applications.
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Antagonizing the calcium-sensing receptor: towards new bone anabolics?
Daniela Riccardi
[FULL-TEXT INQUIRY] [BSP/CMP/E-Pub/00016]

With a rise in the aging population, the global osteoporosis market represents a major unmet need and one of the greatest challenges for the pharmaceutical companies. Currently bisphosphonates constitute the mainstay anti-osteoporotic treatment. They inhibit osteoclast-dependent bone resorption, and substantially reduce the risk of vertebral and non-vertebral fractures. However, bisphosphonates are only marginally effective in subjects with significant loss of bone mineral density. Furthermore, safety concerns have recently been raised due to an increased risk of low-energy fractures associated with long-term bisphosphonate treatment; hence the need for new osteoanabolic drugs. Transient fluctuations in plasma parathyroid hormone (PTH) are a well-established bone anabolic stimulus and efforts have aimed at identifying new medical therapies that can reduce the risk of vertebral and non-vertebral fractures and increase bone mineral density through modifications of circulating PTH. Two approaches have recently emerged in the search for new bone anabolics: a) administration of exogenous PTH, and b) administration of compounds, which evoke transient release of endogenous PTH, namely calcilytics. This review will focus on the potential use of PTH modifying agents as the new osteoanabolics.
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Potential Anti-catabolic and Anabolic Properties of Strontium Ranelate
Romuald Mentaverri, Michel Brazier, Said Kamel, Patrice Fardellone
[FULL-TEXT INQUIRY] [BSP/CMP/E-Pub/00017]

Osteoporosis is a major public health problem for adults above 55 years of age, which leads to an increase in bone fragility. Last decade has witnessed remarkable advances in molecular biology and genetics that led to detailed understanding of the bone remodeling cycle and new therapeutic targets for its treatment have emerged. Thus, besides classical approach (vitamin D and calcium administration, bisphosphonates, oestrogen, raloxifene), new therapeutic  agents such as parathyroid hormone (PTH) compounds, anti-RANKL antibodies and strontium ranelate are or will be increasingly used in treatment of osteoporosis. In this review, we have presented the importance and therapeutic potential of strontium ranelate as a dual agent in the current treatment of osteoporosis.
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Activin Receptor Signaling: A Potential Therapeutic Target for Osteoporosis
Sutada Lotinun, R. Scott Pearsall, William C. Horne, Roland Baron
[FULL-TEXT INQUIRY] [BSP/CMP/E-Pub/00018]

Current antiresorptive therapies not only prevent bone loss by decreasing osteoclastic bone resorption but also inhibit bone formation.  Dual anabolic antiresorptive agents may be required to cure severe osteoporosis by preventing further bone loss and increasing bone mass to normal levels.  Recent studies have demonstrated that activin signaling plays a crucial role in the skeleton.  Activins, like other TGF-β superfamily members, transduce their signals through type I and II receptor serine/threonine kinases.  The binding of activins to activin type IIA (ActRIIA) or type IIB (ActRIIB) receptors induces the recruitment and phosphorylation of an activin type I receptor (ALK4 and/or ALK7), which then phosphorylates the Smad2 and Smad3 intracellular signaling proteins.  Activin signaling is down-regulated by inhibins, follistatin and other proteins, which antagonize activin signaling by a variety of mechanisms. A soluble chimeric protein composed of the extracellular domain of ActRIIA fused to IgG-Fc binds to circulating ligands such as activin A and prevents signaling through the endogenous receptor. In cynomolgus monkeys, the ActRIIA soluble receptor increases bone volume by decreasing bone resorption and increasing bone formation, leading to enhanced mechanical strength and bone quality.  In addition, a single dose of the soluble ActRIIA-Fc fusion protein increased serum BSALP and PINP and decreased serum CTX and TRACP 5b in postmenopausal women.  These data provide evidence of a dual anabolic antiresorptive effect of the soluble ActRIIA-Fc fusion protein in the skeleton.  Therefore, targeting activin receptor signaling may be useful for therapeutic intervention in osteoporosis.  
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Naturally plant-derived compounds: role in bone anabolism
Marie-Noëlle Horcajada and Elizabeth Offord
[FULL-TEXT INQUIRY] [BSP/CMP/E-Pub/00019]

From a nutritional point of view, several factors are involved in ensuring optimal bone health. The most documented of these are calcium and vitamin D. However, it is now well acknowledged that some phytochemicals, also known as phytonutrients, which are plant-based compounds that are present in our daily diet, can positively regulate a number of physiological functions in mammalian systems involved in chronic diseases such as osteoporosis.

Indeed, emerging data in animal models of postmenopausal osteoporosis has shown that exposure to some of these naturally plant-derived compounds (e.g. flavonoids) positively influences bone metabolism through preserved bone mineral density. In vitro experiments with bone cells have reported cellular and molecular mechanisms of phytonutrients involved in bone metabolism. Indeed, phytonutrients and especially polyphenols can act on both osteoblasts and osteoclasts to modulate bone metabolism, a balance between both cell type activities being required for bone health maintenance. To date, most studies investigating the effects of polyphenols on osteoblast cells have reported involvement of complex networks of anabolic signalling pathways such as BMPs or estrogen receptor mediated pathways.

This review will report on the interaction between phytochemicals and bone metabolism in cell or animal models with a particular focus on the molecular mechanisms involved in the bone anabolic response.
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Editorial: PPAR Ligands and Cardiovascular Disorders: Friend or Foe
Pitchai Balakumar and Gowraganahalli Jagadeesh
[BSP/CMP/E-Pub/00020]

INTRODUCTION

Cardiovascular disease (CVD) is the major cause of mortality in patients with metabolic disorders such as obesity and type 2 diabetes mellitus (T2DM). The metabolic disorders associated with abnormal elevated levels of lipids and glucose have strong relationship with the development of CVD [1,2]. This raises important questions about the underlying pathophysiologic events, especially for designing targeted therapeutic interventions to prevent metabolic abnormalities-linked CVD.

The peroxisome proliferator-activated receptor (PPAR) family in mammals is comprised of PPARδ(NR1C1), PPARβ/δ (NR1C2) and PPARγ (NR1C3) subtypes, and a plethora of evidence implicates their key roles in regulation of lipid and glucose metabolism in various organs, including heart and blood vessels. Activation of PPARα induces lipid metabolism and regulates energy homeostasis, whereas the activation of PPARγ causes insulin sensitization, followed by glucose metabolism. On the other hand, activation of PPARβ/δ enhances fatty acid metabolism. Numerous laboratory and clinical studies have exemplified the beneficial effects of PPARα and PPARγ ligands in preventing the cardiovascular risks [reviewed in 3]. Although PPARγ agonists are very effective antidiabetic drugs, serious adverse effects (such as cardiovascular, osteoporosis, bladder tumors, weight gain, signs of myopathy, fluid retention, and peripheral edema) have led to withdrawal of PPARγ agonist, rosiglitazone [4] and restrictions on the use of another PPARγ agonist, pioglitazone. These safety concerns were a set back on the development of new PPARγ agonists. In this special issue of Current Molecular Pharmacology, we address the pharmacologic modulation of PPAR activities by ligands that have potential effects on lipid and glucose metabolism in complex cardiometabolic diseases. For this issue, researchers in this area were invited to contribute results of their work, which would foster the development new PPAR ligands with preserved or improved efficacy but reduced adverse events. 

FUNCTIONAL REGULATION OF PPARs

PPARs are ligand-activated transcription factors belonging to the nuclear hormone receptor superfamily that exhibit different tissue distribution and functions. PPARα is chiefly expressed in tissues with a high oxidative-metabolic capacity such as liver and heart, whereas PPARγ is mostly expressed in adipose tissue with some extent to liver and heart, and the expression of PPARβ/δ is considered ubiquitous. Upon ligand-binding, PPAR recruits a co-activator that removes a co-repressor from the complex, resulting in expression of metabolic genes through a process of heterodimerization with retinoid-X receptor (RXR) on specific genes. In detail, PPAR forms heterodimers with RXR (PPAR-RXR) and subsequently activates specific gene transcription by binding specifically to peroxisome proliferator DNA response elements (PPRE). The resultant PPAR-associated expression of genes regulates the energy balance by influencing the metabolism of lipids and carbohydrates [5-7].

PPARα is a molecular target for fibrate class of hypolipidemic agents such as fenofibrate, clofibrate and gemfibrozil, which primarily reduce triglycerides. They also decrease low-density lipoprotein (LDL) and very low-density lipoprotein (VLDL) levels, and consequently increase high-density lipoprotein (HDL) cholesterol levels [8]. On the other hand, PPARγ is a molecular target for thiazolidinedione (often represented as ‘glitazone’) class of insulin-sensitizing agents such as pioglitazone and rosiglitazone, which are employed for treating T2DM with insulin resistance cases. The clinical use of PPARβ/δ agonists as antiobesity and hypolipidemic agents are under investigation and are yet to be approved for clinical use [9,10].

CARDIOPROTECTIVE POTENTIALS OF FENOFIBRATE

Fenofibrate, among the fibrate class of PPARα agonists, is frequently prescribed for the treatment of hypertriglyceridemia and mixed dyslipidemia [11]. During the past decade, fibrates prescriptions increased by 117.1% in the USA. Fenofibrate was the single most frequently dispensed in the class [12]. The importance of fenofibrate in managing metabolic abnormalities-induced CVD has not been adequately addressed in this issue of articles, and therefore, some of the important pleiotropic cardiovascular potentials of fenofibrate are discussed below.

Experimental studies demonstrated numerous pleiotropic effects of fenofibrate in protecting the cardiovascular and renal system [13-16]. Fenofibrate prevented the progression of hypertensive heart disease in rats by reducing myocardial fibrosis, inflammation and cardiac dysfunction [17]. In the pressure-overloaded rat heart, fenofibrate halted the progression of cardiac hypertrophy by reducing expression of mRNA coding for endothelin-1 and collagen type-I and type-III [18]. In angiotensin-II-infused rats, fenofibrate averted the development of hypertension and myocardial inflammation by decreasing cardiac expressions of vascular cell adhesion molecule-1, platelet endothelial cell adhesion molecule and intercellular adhesion molecule-1 [19]. Yuan et al. [20] have shown that fenofibrate attenuated isoproterenol-induced acute myocardial ischemic injury in rats. Mechanistically, fenofibrate markedly prevents the development of experimental vascular endothelial dysfunction by activating endothelial nitric oxide synthase (eNOS), thus generating endothelium-derived relaxing factor (nitric oxide) in the vessel, reducing the oxidative stress, and consequently improving the integrity and function of vascular endothelium [21,22].

Several reports, including the aforementioned experimental studies, suggest the cardioprotective pleiotropic effects of fenofibrate, in addition to its lipid-lowering potential. In fact, recent clinical studies [23,24] substantiate the cardioprotective role of fenofibrate. The Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) trial showed that diabetic patients with marked dyslipidemia (i.e., elevated triglycerides and low HDL cholesterol) were at the highest risk of CVD. Fenofibrate significantly reduced CVD events in those patients with dyslipidemia or hypertension. The prime effect of fenofibrate on reducing CVD risk was observed in subjects having discernible dyslipidemia. On the basis of these findings, the investigators of FIELD trial concluded that the presence of metabolic syndrome components increases CVD risk in individuals with T2DM, and the absolute benefits of fenofibrate are likely to be substantial when the metabolic syndrome features are present. In addition, the highest risk and greatest benefits of fenofibrate were noted in patients with marked hypertriglyceridemia [23]. The FIELD study data recommended the use of fenofibrate monotherapy to prevent CVD events in diabetic atherogenic dyslipidemic patients, preferably without prior microvascular or macrovascular complications. On the contrary, this favorable effect was not observed in patients without atherogenic dyslipidemia [25]. The Action to Control Cardiovascular Risk in Diabetes (ACCORD) study investigated the effect of fenofibrate in combination with simvastatin in patients with T2DM on cardiovascular outcomes [24]. This trial concluded that the combination therapy did not reduce the rate of fatal cardiovascular events and non-fatal myocardial infarction relative to simvastatin monotherapy. Thus, it can be suggested from these studies that fenofibrate alone reduces the CVD risk in diabetic patients with dyslipidemia (high triglycerides and low HDL levels). However, similar beneficial effects of fenofibrate may not be observed in diabetic patients without dyslipidemia.

THIAZOLIDINEDIONES AND RISK OF ISCHEMIC HEART DISEASE

A number of studies have reported potential harmful effects, such as myocardial infarction, heart failure, stroke and peripheral edema, with the use of thiazolidinediones in patients with T2DM [10,26,27]. The risk of serious or severe heart failure with the use of thiazolidinediones in T2DM patients has been confirmed in several meta-analyses [27-30].

In July 2007, the joint advisory committee, constituted with the members of the Endocrinologic and Metabolic Drug Advisory Committee (EMDAC) and the Drug Safety and Risk Management Advisory Committee of the US Food and Drug Administration (FDA), warned that the use of rosiglitazone, a PPARγ agonist, in treating T2DM could be associated with a greater risk of myocardial ischemic events [31]. Subsequently, the FDA added a box warning about rosiglitazone-associated incidence of myocardial ischemic events to the drug product’s label. In July 2010, the joint advisory committee of the FDA has further confirmed rosiglitazone-associated cardiovascular abnormalities, and advised that the risk of acute myocardial infarction is about 30 to 80 percent higher among T2DM patients taking rosiglitazone than those receiving placebo [32]. The precise mechanisms involved in rosiglitazone-induced myocardial infarction are not yet understood, and it is uncertain to how rosiglitazone-mediated PPARγ activation could play a role.

Pioglitazone, another PPARγ agonist, does not appear to increase the risk of myocardial ischemic events in T2DM patients. Intriguingly, there is evidence to suggest that pioglitazone may afford protection against detrimental cardiovascular events in diabetic patients [33,34]. However, in June 2011, the U.S. FDA informed the health care professionals that use of pioglitazone for more than a year may be associated with an increased risk of bladder cancer. According to the FDA and the European Medicines Agency, although there was no overall increased risk of bladder cancer observed with the use of pioglitazone, an increased risk of bladder cancer was noted among diabetic patients with the longest exposure to pioglitazone [35,36]. Recently, two European countries, Germany and France, decided against marketing of pioglitazone because of bladder cancer [37]. These controversial and discouraging reports are in stark contrast to the satisfactory clinical applications of glitazones to T2DM patients with cardiometabolic disorders.

A GLIMPSE OF THE SPECIAL ISSUE

The purpose of this special issue is to provide a forum for new research findings and updates in the area of PPARs, and to enlighten the readers on current advances in the pharmacotherapeutics of PPAR ligands and their prospective role in the management of cardiovascular abnormalities associated with metabolic disorders. This special issue has key contributions from 20 experts from around the globe affiliated to academia, medicine, bio-pharmaceutical industry, and regulatory agencies. It is comprised of nine articles, including this editorial, and it is hoped that this issue will be of immense assistance to the readers of Current Molecular Pharmacology for conveying a better understanding of the current perspectives and future directions of PPAR research pertaining to cardiometabolic disorders. The salient features of this issue have been summarized below.

It is well established that chronic elevations or uncontrolled levels of plasma glucose and lipids elicit a plethora of pathologic effects that cause the progressive structural and functional deterioration of key organs, including the heart and vasculature. Mary Sugden, Mark Warlow and Mark Holness address the metabolic abnormalities leading to cardiac lipotoxicity, oxidative stress and myocardial dysfunction, and the therapeutic benefits of PPARα and PPARγ activation in correcting some of these detrimental effects [38]. It is well known that cardiometabolic syndrome leads to development of atherosclerotic vascular disease, atherogenic dyslipidemia, elevated blood pressure, hyperglycemia, and myocardial proinflammatory and prothrombic states. Although the exact mechanisms involved in the pathogenesis of cardiometabolic syndrome are not yet completely understood, the deregulated PPARs-associated incidences of abdominal/visceral obesity and insulin resistance appear to be the major underlying factors of this detrimental condition. Huang and Basil Roufogalis review the therapeutic opportunities of some of the dual and pan PPAR   agonists, selective PPARγ modulators, PPARβ/δ agonists, and those of natural origin to managing the diabetic heart, atherosclerotic cardiovascular disease and T2DM associated with cardiometabolic syndrome [39]. The next article by Akira Sugawara, Akira Uruno, Ken Matsuda, Tadao Funato, Akiko Saito-Hakoda, Masataka Kudo, and Sadayoshi Ito discusses the effectiveness of PPARγ ligands in hypertension, atherosclerosis, renal dysfunction, and T2DM [40].

A question remains as to whether the risks of PPAR ligands on cardiovascular system could outweigh the potential benefits. Satyam Sarma addresses these imperative issues by discussing cardiac PPAR signaling pathways and key molecular mechanisms that might contribute to adverse events [41]. As noted previously, rosiglitazone has been associated with an increased cardiovascular risk in T2DM patients. Animal models fell short in predicting some of the cardiovascular adverse effects seen in patients treated with a glitazone, e.g., animal models consistently suggested that direct action of PPARγ on the heart could even be beneficial [42]. Xinkang Wang highlights this gap between nonclinical and clinical findings, which may reflect the lack of an appropriate translational model for assessment of specific issues in cardiovascular safety [43].

After the discouraging results of rosiglitazone on the cardiovascular outcomes, pioglitazone is the only available PPARγ agonist for the treatment of T2DM in most countries except Germany and France. It is therefore important to discuss the safety and tolerability of pioglitazone in the treatment of T2DM and associated cardiovascular co-morbidities. Giuseppe Derosa and Pamela Maffioli discuss the potential role of pioglitazone on glycemic control, lipid profile and CVD risk [44]. Recent studies have revealed the modulatory role of PPARγ in regulating the function of vascular endothelium and their influence on vascular tone. Novel effects of PPARγ ligands on vascular tone may play a potential role in combating the progression of metabolic hypertensive heart disorders and blood pressure. This is a new and upcoming research area pertaining to PPAR pharmacology. Salvatore Salomone and Filippo Drago [45] review the available data on PPARγ ligands as modulators of vascular tone to characterize the potential differences in the endothelium-dependent and -independent effects of PPARγ ligands in maintaining vascular tone.

Finally, PPARγ plays an essential role in the regulation of cell proliferation, fibrosis and inflammation. Activation of PPARγ may have a multitude of anti-fibrotic and anti-inflammatory effects. Shizuko Nagao and Tamio Yamaguchi describe with experimental evidence the novel therapeutic value of PPARγ agonists in the treatment of renal and hepatic manifestations and cardiac defects in progressive polycystic kidney disease [46]. Sugawara et al. [40] also highlight the renoprotective effects of PPARγ agonists in various clinical and non-clinical situations. The new pharmacologic strategies should be interpreted with caution because of cardiovascular adverse effects and risk of urinary bladder cancer for pioglitazone.

In conclusion, PPARs are attractive and still relatively unexploited potential target sites for the development of promising drugs as a result of their well-defined regulatory roles in both glucose homeostasis and lipid metabolism. Despite the toxicity concerns, which are invariably compound specific and due to a PPAR unrelated effect, one should not entirely dismiss the vast potential for new compounds targeting the PPAR family in treating cardiometabolic syndrome and associated abnormalities. It is worth to note that we recently suggested that the beneficial effects of statins in treating CVD could be partially mediated by PPARs-dependent mechanisms [47]. Thus, the benefit and risk evaluation of each adverse effect pertaining to PPAR ligands should be examined on a case by case basis.

CONFLICT OF INTEREST

No conflict of interest is declared.

ACKNOWLEDGMENT

The authors wish to thank Drs. Thomas Papoian and Fred K. Alavi (both from the US FDA) for helpful comments on this editorial.

ABBREVIATIONS

CVD = Cardiovascular disease
T2DM = Type 2 diabetes mellitus
PPAR = Peroxisome proliferator-activated receptor
RXR = Retinoid-X receptor
PPRE = Peroxisome proliferator DNA response elements
LDL = Low-density lipoprotein
VLDL = Very low-density lipoprotein
HDL = High-density lipoprotein
eNOS = Endothelial nitric oxide synthase
FIELD = The Fenofibrate Intervention and Event Lowering in Diabetes
ACCORD = The Action to Control Cardiovascular Risk in Diabetes
EMDAC = Endocrinologic and Metabolic Drug Advisory Committee
US FDA = US Food and Drug Administration

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The involvement of PPARs in the causes, consequences and mechanisms for correction of cardiac lipotoxicity and oxidative stress
M.C. Sugden, M.P. Warlow and M.J. Holness
[FULL-TEXT INQUIRY] [BSP/CMP/E-Pub/00021]

Chronically-elevated plasma lipid concentrations, particularly when combined with high glucose, elicit a plethora of effects that cause the progressive deterioration of insulin sensitivity and ultimately cellular malfunction or death. This review addresses how metabolic abnormalities in white adipose tissue leading to excessive lipid or abnormal adipokine release can be modified by PPARγ activation.  It also discusses the etiology of cardiac lipotoxicity and oxidative stress, in relation to imbalanced lipid delivery and clearance and how PPARa activation can be used to correct some of these effects.



Healing the Diabetic Heart: Modulation of Cardiometabolic Syndrome through Peroxisome Proliferator Activated Receptors (PPARs)
Tom Hsun-Wei Huang and Basil D Roufogalis
[FULL-TEXT INQUIRY] [BSP/CMP/E-Pub/00022]

Cardiometabolic syndrome is a mixture of interrelated risk factors predisposing individuals to elevated risk of atherosclerotic cardiovascular disease and type 2 diabetes mellitus. Nuclear receptors, specifically peroxisome proliferator-activated receptors (PPARs), were identified to play a pivotal role in the regulation of metabolic homeostasis. However, with rosiglitazone currently under intense scrutiny great concerns have arisen regarding the safety of the thiazolidinedione PPAR-γ agonist family as a whole. This review discusses the current concern with PPAR-g agonists by exploring if PPARs can still be considered worth pursuing as a viable target for cardiovascular diseases. We examine current research focusing on identifying ligands that are dual and pan-PPAR agonists, selective PPAR-γ modulators, PPAR-β/δ agonists and that are of natural origin.
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Effects of PPARγ agonists against vascular and renal dysfunction
Akira Sugawara, Akira Uruno, Ken Matsuda, Tadao Funato, Akiko Saito-Hakoda, Masataka Kudo and Sadayoshi Ito
[FULL-TEXT INQUIRY] [BSP/CMP/E-Pub/00023]

Peroxisome proliferator-activated receptor (PPAR)γ, a nuclear hormone receptor, is activated by its agonists including anti-diabetic thiazolidinediones, and has recently been reported to exert beneficial effects in the vasculature independently of its anti-diabetic effects. We here discuss our recent findings on the beneficial pleiotropic effects of PPARγ agonists. PPARγ agonists have been shown to lower blood pressure in both animals and humans, which may possibly be mediated via the PPARγ agonist-mediated inhibition of the renin-angiotensin-aldosterone system (RAAS) including the suppression of angiotensin (Ang) II type 1 receptor expression/Ang II-mediated signaling pathways and Ang II-induced adrenal aldosterone synthesis/secretion. PPARγ agonists also inhibited the progression of atherosclerosis in both animals and humans. PPARγ agonist-mediated inhibition of the RAAS and the thromboxane A₂ system as well as endothelial protection may possibly be involved in the inhibitory effects on blood pressure and atherosclerosis. Furthermore, PPARγ agonists were demonstrated to have reno-protective effects, especially in reducing proteinuria in diabetic nephropathy in both animals and humans. The reno-protective effects of PPARγ agonists were also observed in non-diabetic renal dysfunctions. The effects may possibly be mediated via the PPARγ agonist-mediated blood pressure lowering, endothelial protection, and vasodilation of the glomerular efferent arterioles.. Additionally, anti-neoplastic effects of PPARγ agonists have recently received much attention. PPARγ agonists, may therefore, be useful and effective against lifestyle-related diseases.
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Use of clinically available PPAR agonists for heart failure; do the risks outweigh the potential benefits?
Satyam Sarma
[FULL-TEXT INQUIRY] [BSP/CMP/E-Pub/00024]

PPAR agonists represent a heterogeneous group of compounds that have been used in the treatment of cardiovascular and metabolic diseases for over thirty years. While the primary indications for PPAR agonist therapy focus on hyperlipidemia and diabetes, there is a growing body of pre-clinical data that suggests they may be beneficial in the treatment of heart failure; a disease marked by abnormal myocardial metabolism, fibrosis and insulin insensitivity. PPAR agonist treatment in numerous animal models of systolic heart failure have demonstrated improvement in cardiac function with decreased fibrosis, improved contractility and endothelial function. However considerable controversy exists on the cardiac safety profile of PPAR agonists, particularly concern for inducing lipotoxicty and precipitating or worsening heart failure. In addition during pre-clinical testing, many compounds have been associated with increased death and adverse cardiovascular outcomes casting a pall over their future use for treating disorders of myocardial function. This article will review cardiac pathways involved in PPAR activation and their potential regulation of maladaptive pathways involved in heart failure and highlight molecular mechanisms that may contribute to adverse events and raise safety concerns. Specific attention will be focused on PPAR alpha and gamma, subtypes for which commercially available PPAR agonists are currently available.
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Assessment of cardiac safety for PPARγ agonists in rodent models of heart failure: A translational medicine perspective
Xinkang Wang
[FULL-TEXT INQUIRY] [BSP/CMP/E-Pub/00025]

PPARγ-modulators, a class of anti-diabetic drugs as represented by thiazolidinediones (TZD), have been associated with cardiovascular risks in type-2 diabetes in humans but a similar liability has not been demonstrated in preclinical models. This gap between clinical and preclinical observations may reflect the lack of a translational model for cardiac safety assessment because preclinical efficacy for glycemic control for PPARγ-modulators is routinely conducted in animals with diabetic background while drug safety study is performed in young and health animals with little risk of heart failure, in contrast to the complex pathophysiological conditions of patients subjected to the treatment of TZDs.  Therefore, some key steps are important to address this translational gap. First, it is essential to use an appropriate translational model that mimics most of human pathophysiology for the assessment of cardiovascular safety for TZDs. Second, it calls for the discovery of a translational biomarker (most likely a collection of biomarkers due to multiple risk factors contributed to the complex disease) to be able to sensitively detect the disease progression and in response to therapy. Specific examples are provided in this review for the use of a rodent model of myocardial infarction-induced heart failure to address the cardiac safety concern in response to chronic treatment of rosiglitazone. Multiple biomarkers, including physiological, biochemical, pharmacogenomic and imaging biomarkers, were applied to assess the cardiovascular risk in this heart failure model.  The data and strategic approach are discussed from translational medicine perspectives.
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Peroxisome Proliferator-Activated Receptor-γ (Ppar-γ) Agonists On Glycemic Control, Lipid Profile And Cardiovascular Risk
Giuseppe Derosa and Pamela Maffioli
[FULL-TEXT INQUIRY] [BSP/CMP/E-Pub/00026]

Peroxisome proliferator-activated receptor (PPAR) is involved in the pathology of numerous diseases including obesity, diabetes, and atherosclerosis, because of its role in decreasing insulin resistance and inflammation. Type 2 diabetes mellitus and obesity are the most frequent endocrine-metabolic diseases and their pathogenic basis are characterized by insulin resistance and insulin secretion defects that can be demonstrated through several alterations in carbohydrates, lipids, and protein metabolism. For that reason a class of compounds, called thiazolidinediones, has been developed for the management of type 2 diabetes mellitus. Thiazolidinediones are PPAR-γ agonists regulating the expression of several genes involved in the regulation of glucose, lipid and protein metabolism, enhancing the action of insulin in insulin-sensitive tissue by increasing glucose uptake in skeletal muscle and adipose tissue, and decreasing hepatic glucose production. Pioglitazone is the only available PPAR-γ agonist for the treatment of type 2 diabetes after rosiglitazone withdrawal from several countries. This review discusses the safety and effectiveness of pioglitazone in the clinical practice for the treatment of type 2 diabetes mellitus.
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Effects of PPARγ ligands on vascular tone
Salvatore Salomone and Filippo Drago
[FULL-TEXT INQUIRY] [BSP/CMP/E-Pub/00027]

Peroxisome Proliferator-Activated Receptor γ  (PPARγ), originally described as a transcription factor for genes of carbohydrate and lipid metabolism, has been more recently studied in the context of cardiovascular pathophysiology. Here, we review the available data on PPARγ ligands as modulator of vascular tone. PPARγ ligands include: thiazolidinediones (used in the treatment of type 2 diabetes mellitus), glitazars (bind and activate both PPARγ and PPARα), and other experimental drugs (still in development) that exploit the chemistry of thiazolidinediones as a scaffold for PPARγ-independent pharmacological properties. In this review, we examine both short (mostly from in vitro data)- and long (mostly from in vivo data)-term effects of PPARγ ligands that extends  from PPARγ-independent vascular effects to PPARγ-dependent gene expression. Because endothelium is a master regulator of vascular tone, we have attempted to differentiate between endothelium-dependent and endothelium-independent effects of PPARγ ligands. Based on available data, we conclude that PPARγ ligands appear to influence vascular tone in different experimental paradigms, most often in terms of vasodilatation (potentially increasing blood flow to some tissues). These effects on vascular tone, although potentially beneficial, must be weighed against specific cardiovascular warnings that may apply to some drugs, such as rosiglitazone.
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PPARγagonists in polycystic kidney disease with frequent development of cardiovascular disorders
Shizuko Nagao and Tamio Yamaguchi
[FULL-TEXT INQUIRY] [BSP/CMP/E-Pub/00028]

Autosomal dominant polycystic kidney disease (ADPKD) is the most common of the monogenic disorders and is characterized by bilateral renal cysts; cysts in other organs including liver, pancreas, spleen, testis and ovary; vascular abnormalities including intracranial aneurysms and subarachnoid hemorrhage; and cardiac disorders such as left ventricular hypertrophy (LVH), mitral valve regurgitation, mitral valve prolapse and aortic regurgitation.  Autosomal recessive polycystic kidney disease (ARPKD) is an early-onset multisystem disorder characterized by polycysts divided from the renal collecting ducts, congenital hepatic fibrosis, and ductal plate malformation complicated by pulmonary hyperplasia and systemic hypertension.  In these polycystic kidney diseases (PKD), progressive enlargement of the cysts results from the aberrant proliferation of tubule epithelial cells and trans-epithelial fluid secretion leading to extensive nephron loss and interstitial fibrosis.  Peroxisome proliferator-activated receptor-γ (PPAR-γ), a member of the ligand-dependent nuclear receptor superfamily, is expressed in a variety of tissues, including kidneys and liver, and plays important roles in cell proliferation, fibrosis, and inflammation.  PPAR-γ agonists ameliorate polycystic kidney, polycystic liver and cardiac defects through β-catenin, c-Myc, CFTR, MCP-1, S6, ERK, and TGF-β signaling pathways in animal models of PKD.  In this review, we describe the possible therapeutic value of PPAR-γ agonists in the treatment of renal and hepatic manifestations, and cardiac defects in progressive PKD.
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The application of mass spectrometry to proteomics and metabolomics in biomarker discovery and drug development
Toshiyuki Mikami, Mikio Aoki and Toru Kimura
[FULL-TEXT INQUIRY] [BSP/CMP/E-Pub/00029]

Drugs are launched to market after the lengthy process of development. Despite careful preclinical assessment, there is still a significant risk that a drug candidate may elicit adverse effects or display a low level of efficacy during clinical trials. If a drug candidate fails in the latter stages of the clinical process, the overall loss, both in terms of time and money, is enormous. A major concern for the pharmaceutical companies is to improve the drug development process to make it faster and more cost-effective by adoption of new technologies. Biomarkers are emerging as a key tool in identifying potential drug failures at an early stage or in helping to make go/no-go decisions, which should significantly accelerate drug development. Omics technologies play an important role in biomarker discovery as well as in other stages of the drug discovery and development (e.g. target discovery, mechanism of action or predicting toxicity). In particular, recent progress in mass spectrometry techniques such as selected reaction monitoring (SRM) and novel high-resolution features have helped facilitate the realization of the inherent power of proteomics and metabolomics in biomarker discovery, validation and qualification. In this manuscript, we review the current state of proteomics and metabolomics in conjunction with recent technical advances in mass spectrometry with some examples of applications in biomarker research. In addition, we discuss the possible impact of biomarker research with these technologies in drug discovery and development.
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Editorial:
Dr. Srinivasan Madhusudan
[BSP/CMP/E-Pub/00030]


INTRODUCTION

The overall prognosis for advanced cancer remains poor. Although chemotherapy, radiotherapy and targeted agents have significantly improved patient outcomes, treatment related toxicity and the emergence of resistance negatively impact on survival. The therapeutic efficacy of many chemotherapeutic agents and ionising radiation is determined by their ability to induce DNA damage in cells. However, the DNA repair capacity of cancer cells to repair DNA damage induced by cytotoxic agents may directly influence treatment efficacy and resistance. Therefore, pharmacological inhibition of DNA repair in cancer cells has the potential to influence tumour response and clinical benefit to patients [1, 2].

The potential of DNA repair inhibitors has been confirmed in preclinical and clinical studies using Poly(ADP-ribose) polymerase (PARP) inhibitors. [3-8]. PARPs are involved in the regulation of several cellular pathways including DNA base excision repair (BER) [9]. Tumours that are deficient in homologous recombination (HR) DNA repair pathway (tumours in patients with germline mutations in the BRCA1 or BRCA2 genes) are dependent upon other DNA repair pathways such as BER for survival. However therapeutic inhibition of BER using PARP inhibitors  leads to the selective killing of  BRCA1 or BRCA-2 tumour cell in the absence of any cytotoxic agent. The ability of PARP inhibitors to induce synthetic lethality in BRCA deficient breast and ovarian cancer suggests that other factors within BER are also potential synthetic lethality targets. Moreover, the ability of BER modulation to enhance cytotoxicity of alkylating agents and ionising radiation provides further evidence that BER factors are also likely to be promising targets to enhance therapeutic efficacy of anti-cancer agents.

This exciting hot topic issue in Current Molecular Pharmaoclogy has brought together leading experts in the field to review the current status of BER in cancer therapy. As several reviews have been published recently on PARP inhibitors [5-8] we have decided to focus on BER targets other than PARP in this issue. Yun-Jeong Kim and David M.Wilson III have set the scene with an overview of BER biochemistry. BER pathway is complex and is usually initiated by a damage specific DNA glycosylase, which removes the damaged base creating an abasic site (apurinic/apyrimidinic, AP site). AP endonuclease (APE1) then cleaves the phosphodiester bond 5β to the AP site thereby generating a nick with 5β-sugar phosphate (dRP) and 3β-hydroxyl group. Members of the poly (ADP-ribose) polymerase (PARP) family of proteins get activated by single strand DNA breaks induced by APE1 and catalyze the addition of poly (ADP-ribose) polymers to target proteins, affecting protein-protein interactions. DNA polymerase b adds the first nucleotide to the 3β-end of the incised AP site. Normally, the reaction continues through the short-patch repair pathway where Pol b removes the 5β-sugar phosphate residue (by the process of β-elimination) and DNA ligase III-XRCC1 heterodimer (or DNA ligase I) then completes the repair [10-17].

AP sites are obligatory intermediates in the pathway for repair of alkylated bases (caused by alkylating agents such as temozolomide) and oxidized DNA bases (caused by ionising radiation)[18]. Unrepaired AP sites are cytotoxic and affect genomic integrity. In BER, AP sites are processed by AP endonucleases (APE1). APE1 is a multifunctional protein. The DNA repair function is performed by the C-terminal domain whereas the N-terminal domain is involved in redox regulation of transcription factors. Emerging preclinical and clinical data confirm that both C-terminal and N-terminal domains of APE1 are promising new drug targets. Odde et al. have reviewed the current status of APE1 DNA repair domain inhibitors in preclinical development. Kelley and co-workers have summarized the translational application of APE1 redox domain inhibitors in cancer. DNA polymerase b is also a promising drug target in BER. The biological relevance of Pol β and translesional synthesis is discussed by Nocolay et al. Strategies to impair Pol β function in cancer therapy has been reviewed in detail by Goellner et al.  It is increasingly clear that control of redox homeostasis impacts upon oxidative base damage. Storr and co-workers discuss the interesting links between DNA repair and redox regulation and applications to cancer therapy. Temozolomide is an important alkylating agent used in cancer therapy. The mechanisms of action of temozolomide, resistance mechanisms and strategies to bypass such resistance that impair therapeutic efficacy are discussed by Zhang et al. The narrow therapeutic index and the heterogeneity of patient responses to chemotherapy and radiotherapy imply that the efficacy of these agents could potentially be tailored based on tumour biology using predictive biomarkers. Gossage et al. provide the clinical evidence to support the view that BER factors are promising prognostic and predictive markers in cancer and could influence personalized cancer therapy in the future.

In conclusion, this hot topic issue is the first comprehensive summary of emerging drug targets in BER and will provide essential information for basic scientists, pharmaceutical scientists and clinicians interested in  cancer therapy. DNA repair is the next new frontier in anti-cancer discovery. A concerted collaborative effort by the pharmaceutical industry and academic research groups will help accelerate drug development targeting DNA repair in the near future.


References:


[1] Madhusudan, S.; Middleton, M.R. The emerging role of DNA repair proteins as predictive, prognostic and therapeutic targets in cancer. Cancer Treat. Rev., 2005, 31, 603-617.
[2] Madhusudan, S.; Hickson, I.D. DNA repair inhibition: a selective tumour targeting strategy. Trends Mol. Med., 2005, 11, 503-511.
[3] Bryant, H.E; Schultz, N.; Thomas, H.D, Parker, K.M.; Flower, D.; Lopez, E.; Kyle, S.; Meuth, M.; Curtin, N.J.; Helleday, T. Specific killing of BRCA2-deficient tumours with inhibitors of poly(ADP-ribose) polymerase. Nature, 2005, 434, 913-917.
[4] Farmer, H.; McCabe, N.; Lord, C.J.;Tutt, A.N.; Johnson, D.A.; Richardson, T.B.; Santarosa, M.; Dillon, K.J; Hickson, I.; Knights, C.; Martin, N.M.; Jackson, S.P.; Smith, G.C.; Ashworth, A. Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy. Nature, 2005, 434, 917-921.
[5] Martin, S.A.; Lord, C.J.; Ashworth, A. DNA repair deficiency as a therapeutic target in cancer. Curr. Opin. Genet. Dev., 2008, 18, 80-86.
[6] Rehman, F.L.; Lord, C.J.; Ashworth, A. Synthetic lethal approaches to breast cancer therapy. Nat. Rev. Clin. Oncol., 7, 718-724.
[7] Lord, C.J.; Ashworth, A. Targeted therapy for cancer using PARP inhibitors. Curr. Opin. Pharmacol., 2008, 8, 363-369.
[8] Banerjee, S.; Kaye, S.B.; Ashworth, A. Making the best of PARP inhibitors in ovarian cancer. Nat. Rev. Clin. Oncol., 7, 508-519.
[9] Jagtap, P.; Szabo, C. Poly(ADP-ribose) polymerase and the therapeutic effects of its inhibitors. Nat. Rev. Drug Discov., 2005, 4, 421-440.
[10] Sancar, A,; Lindsey-Boltz, L.A.; Unsal-Kacmaz, K.; Linn, S. Molecular mechanisms of mammalian DNA repair and the DNA damage checkpoints. Annu. Rev. Biochem., 2004, 73, 39-85.
[11] Barnes DE, Lindahl T. Repair and genetic consequences of endogenous DNA base damage in mammalian cells. Annu. Rev. Genet., 2004, 38, 445-476.
[12] Fortini, P.; Pascucci, B.; Parlanti, E.; D'Errico, M.; Simonelli, V.; Dogliotti, E. The base excision repair: mechanisms and its relevance for cancer susceptibility. Biochimie, 2003, 85, 1053-1071.
[13] Dianov, G.L. Monitoring base excision repair by in vitro assays. Toxicology, 2003, 193, 35-41.
[14] Dianov, G.L.; Sleeth, K.M.; Dianova, II.; Allinson, S.L. Repair of abasic sites in DNA. Mutat. Res., 2003, 531, 157-163.
[15] Izumi, T.; Wiederhold, L.R.; Roy, G.; Roy, R.; Jaiswal, A.; Bhakat, K.K.; Mitra, S.; Hazra, T.K. Mammalian DNA base excision repair proteins: their interactions and role in repair of oxidative DNA damage. Toxicology, 2003, 193, 43-65.
[16] Nilsen, H.; Krokan, H.E. Base excision repair in a network of defence and tolerance. Carcinogenesis, 2001, 22, 987-998.
[17] Abbotts, R.; Madhusudan, S. Human AP endonuclease 1 (APE1): From mechanistic insights to druggable target in cancer. Cancer Treat. Rev., 36(5): 425-435.
[18] Hickson, I.D. Base Excision Repair of DNA Damage: Landes Bioscience; 1997.
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Overview of Base Excision Repair Biochemistry
Yun-Jeong Kim and David M. Wilson III
[FULL-TEXT INQUIRY] [BSP/CMP/E-Pub/00031]

Base excision repair (BER) is an evolutionarily conserved pathway, which could be considered the “workhorse” repair mechanism of the cell.  In particular, BER corrects most forms of spontaneous hydrolytic decay products in DNA, as well as everyday oxidative and alkylative modifications to bases or the sugar phosphate backbone.  The repair response involves five key enzymatic steps that aim to remove the initial DNA lesion and restore the genetic material back to its original state:  (i) excision of a damaged or inappropriate base, (ii) incision of the phosphodiester backbone at the resulting abasic site, (iii) termini clean-up to permit unabated repair synthesis and/or nick ligation, (iv) gap-filling to replace the excised nucleotide, and (v) sealing of the final, remaining DNA nick.  These repair steps are executed by a collection of enzymes that include DNA glycosylases, apurinic/apyrimidinic endonucleases, phosphatases, phosphodiesterases, kinases, polymerases and ligases.  Defects in BER components lead to reduced cell survival, elevated mutation rates, and DNA-damaging agent hypersensitivities.  In addition, the pathway plays a significant role in determining cellular responsiveness to relevant clinical anti-cancer agents, such as alkylators (e.g. temozolomide), nucleoside analogs (e.g. 5-fluorouracil), and ionizing radiation.  The molecular details of BER and the contribution of the pathway to therapeutic agent resistance are reviewed herein.
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Small-Molecule Inhibitors of APE1 DNA Repair Function: An Overview
Rasha I. Al-Safi,  Srinivas Odde,  Yumna Shabaik and Nouri Neamati
[FULL-TEXT INQUIRY] [BSP/CMP/E-Pub/00032]

APE1 is a multifaceted protein that orchestrates multiple activities in the cell, one of which is the preservation of genomic integrity; a vital process that takes place in the context of the base excision repair (BER) pathway. Studies have also implicated APE1 in rendering cancerous cells less vulnerable to the effects of DNA-damaging agents that are commonly used for the treatment of cancer. Furthermore, suppression of APE1expression in cancer cell lines is accompanied by the potentiation of the activity of cytotoxic agents. As a result, major efforts have been directed towards the identification of small-molecule inhibitors of this DNA-repair enzyme. Herein, we review all patented small-molecule APE1 inhibitors reported prior to 2011. Unfortunately, the potency and selectivity of many of the reported inhibitors were not disclosed by the original authors, and at present it is unclear if APE1 is a bona fide target for many of the purported inhibitors. Moreover, cellular activity and toxicity of many inhibitors remains to be established. Since this is the first comprehensive review of small molecule APE1 inhibitors, we present all compounds reported to inhibit APE1 activity with an IC₅₀ value ≤ 25 μM. Efforts towards a careful validation and optimization of these compounds is warranted. Furthermore, we explore potential allosteric drug-binding sites on the protein as an alternative approach for modulating the activity of this multifunctional protein. Finally, we give an overview of APE2 as well as other homologues in some disease-causing pathogens. Given the role of DNA repair in pathology, we propose exploiting the highly conserved DNA repair domains of these proteins by potentially targeting these domains with the herein discussed small-molecules originally studied for APE1, thereby greatly increasing their prospective application for various diseases.
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APE1/Ref-1Role in Redox Signaling: Translational Applications of Targeting the Redox Function of the DNA Repair/Redox Protein APE1/Ref-1
Mark R. Kelley, Millie M. Georgiadis and Melissa L. Fishel
[FULL-TEXT INQUIRY] [BSP/CMP/E-Pub/00033]

The heterogeneity of most cancers diminishes the treatment effectiveness of many cancer-killing regimens. Thus, treatments that hold the most promise are ones that block multiple signaling pathways essential to cancer survival. One of the most promising proteins in that regard is APE1, whose reduction-oxidation activity influences multiple cancer survival mechanisms, including growth, proliferation, metastasis, angiogenesis, and stress responses. With the continued research using APE1 redox specific inhibitors alone or coupled with developing APE1 DNA repair inhibitors it will now be possible to further delineate the role of APE1 redox, repair and protein-protein interactions. Previously, use of siRNA or over expression approaches, while valuable, do not give a clear picture of the two major functions of APE1 since both techniques severely alter the cellular milieu. Additionally, use of the redox-specific APE1 inhibitor, APX3330, now makes it possible to study how inhibition of APE1’s redox signaling can affect multiple tumor pathways and can potentiate the effectiveness of existing cancer regimens. Because APE1 is an upstream effector of VEGF, as well as other molecules that relate to angiogenesis and the tumor microenvironment, it is also being studied as a possible treatment for age-related macular degeneration and diabetic retinopathy. This paper reviews all of APE1’s functions, while heavily focusing on its redox activities. It also discusses APE1’s altered expression in many cancers and the therapeutic potential of selective inhibition of redox regulation, which is the subject of intense preclinical studies.
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Biological Relevance of DNA Polymerase Beta and Translesion Synthesis Polymerases to Cancer and its Treatment
Nils H. Nicolay, Thomas Helleday and Ricky A. Sharma
[FULL-TEXT INQUIRY] [BSP/CMP/E-Pub/00034]

The cellular genome is constantly subject to DNA damage caused by endogenous factors or exogenously by damaging agents such as ionizing radiation or various anticancer agents.  The base excision repair (BER) enzyme, DNA polymerase β, and the polymerases involved in translesion synthesis (TLS) have been shown to contribute to cellular tolerance and repair of DNA lesions by anticancer treatments, particularly the platinum cytotoxic drugs.  Moreover, there is robust preclinical evidence linking alterations in DNA pol β and TLS polymerase levels to cancer.  DNA polymerases may therefore be potential targets to increase the sensitivity of cancer cells to chemotherapy drugs. In this article, the physical and chemical properties of DNA polymerase β and the translesion synthesis polymerases are reviewed with a view to identifying how they may act as targets for anticancer treatment. The potential clinical role of new DNA polymerase inhibitors is discussed and how they may be combined with conventional cytotoxic agents.
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Targeting DNA Polymerase β for therapeutic intervention
Eva M. Goellner, David Svilar, Karen H. Almeida and Robert W. Sobol
[FULL-TEXT INQUIRY] [BSP/CMP/E-Pub/00035]

DNA damage plays a causal role in numerous disease processes. Hence, it is suggested that DNA repair proteins, which maintain the integrity of the nuclear and mitochondrial genomes, play a critical role in reducing the onset of multiple diseases, including cancer, diabetes and neurodegeneration. As the primary DNA polymerase involved in base excision repair, DNA polymerase β (Polβ) has been implicated in multiple cellular processes, including genome maintenance and telomere processing and is suggested to play a role in oncogenic transformation, cell viability following stress and the cellular response to radiation, chemotherapy and environmental genotoxicants. Therefore, Polβ inhibitors may prove to be effective in cancer treatment. However, Polβhas a complex and highly regulated role in DNA metabolism. This complicates the development of effective Polβ-specific inhibitors useful for improving chemotherapy and radiation response without impacting normal cellular function. With multiple enzymatic activities, numerous binding partners and complex modes of regulation from post-translational modifications, there are many opportunities for Polβ inhibition that have yet to be resolved. To shed light on the varying possibilities and approaches of targeting Polβ for potential therapeutic intervention, we summarize the reported small molecule inhibitors of Polβ and discuss the genetic, biochemical and chemical studies that implicate additional options for Polβ inhibition. Further, we offer suggestions on possible inhibitor combinatorial approaches and the potential for tumor specificity for Polβ-inhibitors.
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Base excision repair, the redox environment and therapeutic implications
Sarah J. Storr, Caroline M. Woolston and Stewart G. Martin
[FULL-TEXT INQUIRY] [BSP/CMP/E-Pub/00036]

Control of redox homeostasis is crucial for a number of cellular processes with deregulation leading to a number of serious consequences including oxidative damage such induction of DNA base lesions. The DNA lesions caused by oxidative damage are principally repaired by the base excision repair (BER) pathway. Pharmacological inhibition of BER is becoming an increasingly active area of research with the emergence of PARP inhibitors in cancer therapy. The redox status of the cell is modulated by a number of systems, including a large number of anti-oxidant enzymes who function in the control of superoxide and hydrogen peroxide, and ultimately in the release of the damaging hydroxyl radical. Here we provide an overview of reactive oxygen species (ROS) production and its modulation by anti-oxidant enzymes. The review also discusses the effect of ROS on the BER pathway, particularly in relation to cancer. Finally, as the modulation of the redox environment is of interest in cancer therapy, with certain agents having the potential to reverse chemo- and radiotherapy resistance or treat therapy related toxicity, we discuss redox modulating agents currently under development.
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Temozolomide: Mechanisms of Action, Repair and Resistance
Jihong Zhang, Malcolm FG Stevens and Tracey D Bradshaw
[FULL-TEXT INQUIRY] [BSP/CMP/E-Pub/00037]

ABCB1, ATP-binding cassette protein B1; ADPRT, ADP-ribosyltransferase; AGT, alkylguanine DNA alkyltransferase; AIC, 5-aminoimidazole-4-carboxamide; AP, abasic; APE-1, AP endonuclease-1;BBB, blood brain barrier; BCNU, 1,3-bis-(2-chloroethyl)-1-nitrosourea (Carmustine); BER, base excision repair; CNS, central nervous system; DSB, DNA double strand break; dRp, 5`-deoxyribose phosphate; GBM, glioblastoma multiforme; GST, glutathione-S-transferase; HNPCC, hereditary nonpolyposis colorectal cancer; MDR; multidrug resistance; MGMT, methylguanine DNA methyltransferase; MMR, DNA mismatch repair; MRP, multidrug resistance protein; MSI, microsatellite instability; MTIC, 5-(3-methyltriazen-1-yl)-imidazole-4-carboxamide; NAD+, β-nicotinamide adenine dinucleotide; N3-MeA, N3-methyladenine; N7-MeG, N7-methylguanine; O6-MeG, O6-methylguanine; PARP-1, poly(ADP-ribose)polymerase-1; PTEN, phosphatise and tensin homologue; SSB, DNA single strand break; TMZ, temozolomide; XRCC1, X-ray repair cross-complementing 1.
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Base Excision Repair Factors Are Promising Prognostic And Predictive Markers In Cancer
Lucy Gossage, Christina Perry, Rachel Abbotts and Srinivasan Madhusudan
[FULL-TEXT INQUIRY] [BSP/CMP/E-Pub/00038]

The cytotoxicity of both chemotherapy and radiotherapy is to a large extent directly related to their ability to induce DNA damage. The ability of cancer cells to recognise and repair this damage contributes to therapeutic resistance. Sub-optimal DNA repair in normal tissue may impair normal tissue tolerance. Inter-individual differences in DNA repair pathways may also influence the natural history and progression of cancer and hence prognosis. The base excision repair (BER) pathway has evolved to repair base damage induced by endogenous and exogenous base targeting agents. Polymorphic variants of genes, mRNA expression and alterations in protein expression within BER, may alter DNA repair capacity and influence both cancer progression and clinical responses to chemotherapy and radiotherapy. We discuss the role of BER genes as potential predictive and prognostic markers in human cancer and review the current state of play within this field.
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