Current Medicinal Chemistry (v.16, #10)
Synergetic Bitherapy in Mice with Xenografts of Human Prostate Cancer Using a Methional Mimic (METLICO) and an Aldehyde Dehydrogenase 3 Inhibitor (MATE): Systemic Intraperitoneal (IP) and Targeted Intra-Tumoral (IT) Administration by E. Hiltbrand, G. Fournet, J-P. Giliberto, M-J. Paret, J. Chantepie, D. Morel, J. Gore, U. Reichert, H. Mehier, M-E. Rochedix, G. Quash (1184-1191).
An intraperitoneal (IP) monotherapy in nu/nu mice with subcutaneous xenografts of a human prostate epithelial cancer cell line:DU145 was undertaken with an aldehyde dehydrogenase 3 inhibitor MATE, that is a potent apoptogen on (DU145) in culture but not on their human prostate epithelial normal counterparts  . Tumour growth was slowed down but treatment had to be done 5days/week. To try to potentiate the action of MATE in vivo, a bitherapy was undertaken based on the synergetic apoptotic effect that had been observed previously in culture on DU145 treated with a methional mimic METLICO and DIMATE, an inhibitor of ALDH1 and ALDH3. The bitherapy with METLICO/MATE administered IP was as effective as the monotherapy with MATE alone by IP, but at a 2-fold lower dose of MATE and at a dose of METLICO that had no growth-inhibitory effect as a monotherapy . Hence there was definite synergism with bitherapy. To try to increase the efficacy of bitherapy, it was administered by the intra-tumoral (IT) route using the recently developed 20-bars-pressurized microinjection system from CERMA [16, 17]. IT administration of the bitherapy was indeed more effective than that by IP as regards tumour volumes are concerned. Histopathological analysis of IT-treated tumours confirmed that there were many necrotized zones but intact cells were still present. Approaches for treating a wider zone of tumour tissue by IT-bitherapy are discussed.
Naphthalimides and Azonafides as Promising Anti-Cancer Agents by Laurent Ingrassia, Florence Lefranc, Robert Kiss, Tatjana Mijatovic (1192-1213).
Naphthalimides, a class of compounds which bind to DNA by intercalation, have shown high anti-cancer activity against a variety of murine and more notably human cancer cell lines. Azonafide derivatives are also potential antitumor agents which are structurally related to the naphthalimides. Derivatives of azonafide have shown enhanced activity against various cancer models, especially leukemias, breast cancer and melanoma. Naphthalimides in general and amonafide in particular, are most probably the agents which have been involved in the greatest number of clinical trials without ever acceding to the market because of dose-limiting toxicity. This statement also reflects the immense interest that oncologists have paid to this class of compounds with respect to their anti-cancer potential. While the first generation of naphthalimides were mainly topoisomerse II poisons, some new compounds display novel mechanism of action. In contrast to the most widely used topo II poisons, including etoposide, adriamycin and their analogues, which often induce multi-drug resistance, several naphthalimide-related compounds have been reported not to be affected by this phenomenon. Multi-disciplinary approaches including medicinal chemistry, early toxicology and DMPK, in vivo activity assessment in diverse preclinical models and in-depth mechanism of action deciphering, along with the lessons learnt from previous and currently ongoing clinical trials, have resulted in the generation of a number of novel promising naphthalimide derivatives. It is thus reasonable to expect that members of this class of compounds will reach the oncology market in the near future.
Matrix Metalloproteinases in Respiratory Diseases: From Pathogenesis to Potential Clinical Implications by Smaragda Oikonomidi, Konstantinos Kostikas, Irene Tsilioni, Kalliopi Tanou, Konstantinos Gourgoulianis, Theodoros Kiropoulos (1214-1228).
Matrix metalloproteinases (MMPs) are zinc-endopeptidases responsible for degradation of the extracellular matrix (ECM) components including basement membrane collagen, interstitial collagen, fibronectin, and various proteoglycans, during normal remodeling and repair processes. The turnover and remodeling of ECM must be tightly regulated since excessive or inappropriate expression of MMPs may contribute to the pathogenesis of tissue destructive processes associated with lung inflammation and disease. Despite the fact that our knowledge in the field of MMP biology is rapidly expanding, the role of MMPs in the pathogenesis of lung diseases is still not clear. The aim of the present review is to present the basic principles of MMP biology and, subsequently, to focus on the clinical and experimental evidence related to MMP activity in various lung disorders, including lung cancer, pleural effusions, chronic obstructive pulmonary disease, asthma, acute respiratory distress syndrome and interstitial lung diseases.
Stress-Activated MAP Kinase Cascades in Cellular Senescence by Junichi Maruyama, Isao Naguro, Kohsuke Takeda, Hidenori Ichijo (1229-1235).
In response to progressive telomere shortening in successive cell divisions, normal somatic cells withdraw from the cell cycle and exhibit irreversible growth arrest. This state, called cellular senescence, is induced not only by telomere shortening but also by various physico-chemical stressors that induce DNA damage and chromatin disruption as well as by strong mitogenic signals. Because senescent cells never re-enter the cell cycle, cellular senescence appears to prevent malignant transformation of damaged cells and thus contributes to tumor suppression. On the other hand, excess accumulation of senescent cells attenuates the integrity and normal function of tissues, leading to age-related diseases. In addition to the well-established roles of p53 and pRB in cellular senescence, recent evidence suggests that stress-activated mitogen- activated protein kinase (MAPK) cascades that converge on c-Jun N-terminal kinases (JNKs) and p38 MAPKs also play important roles in the regulation of cellular senescence. In this review, we focus on signaling that regulates stressinduced cellular senescence, with special focus on the JNK and p38 MAPK cascades.
Erythropoiesis Stimulating Agents and Techniques: A Challenge for Doping Analysts by W. Jelkmann (1236-1247).
Recombinant human erythropoietin (rHuEPO) engineered in Chinese hamster ovary (CHO) cell cultures (Epoetin alfa and Epoetin beta) and its hyperglycosylated analogue Darbepoetin alfa are known to be misused by athletes. The drugs can be detected by isoelectric focusing (IEF) and immunoblotting of urine samples, because and#x201C;EPOand#x201D; is in reality a mixture of isoforms and the N-glycans of the recombinant products differ from those of the endogenous hormone. However, there is a plethora of novel erythropoiesis stimulating agents (ESAs). Since the originator Epoetins alfa and beta are no longer protected by patent in the European Union, rHuEPO biosimilars have entered the market. In addition, several companies in Asia, Africa and Latin America produce copied rHuEPOs for clinical purposes. While the amino acid sequence of all Epoetins is identical, the structure of their glycans differs depending on the mode of production. Some products contain more acidic and others more basic EPO isoforms. Epoetin delta is special, as it was engineered by homologous recombination in human fibrosarcoma cells (HT-1080), thus lacking N-glycolylneuraminic acid like native human EPO. ESAs under development include EPO fusion proteins, synthetic erythropoiesis stimulating protein (SEP) and peptidic (HematideTM, CNTO 528) as well as non-peptidic EPO mimetics. Furthermore, preclinical respectively clinical trials have been performed with small orally active drugs that stimulate endogenous EPO production by activating the EPO promoter (and#x201C;GATA-inhibitorsand#x201D;: diazepane derivatives) or enhancer (and#x201C;HIF-stabilizersand#x201D;: 2-oxoglutarate analogues). The prohibited direct EPO gene transfer may become a problem in sports only in the future.
Nucleic Acid Aptamers Based on the G-Quadruplex Structure: Therapeutic and Diagnostic Potential by B. Gatto, M. Palumbo, C. Sissi (1248-1265).
Aptamers are short DNA- or RNA-based oligonucleotides selected from large combinatorial pools of sequences for their capacity to efficiently recognize targets ranging from small molecules to proteins or nucleic acid structures. Like antibodies, they exhibit high specificity and affinity for target binding. As a result, they may display effective interference in biological processes, which renders them not only valuable diagnostic tools, but also promising therapeutic agents. In fact, one aptamer that inhibits human VEGF already received approval for the treatment of age-related macular degeneration, while several others are undergoing clinical trials. Aptamers display a large number of structural arrangements, which accounts for their binding efficiency and selectivity for unrelated targets. Among several architectures, the Gquadruplex (G-4) is adopted by several aptamers, the most popular of which shows inhibitory properties against thrombin, a pharmacologically relevant protein. G-4 structures consist of planar arrays of four guanines, each guanine pairing with two neighbours by Hoogsteen bonding. Recent work shows that G-4 arrangement is highly polymorphic and therefore represents a large family of stable structures with a common overall fold, but with well differentiated recognition elements that allow prominent diversity to be explored. Conformational plasticity consents fine tuning of target recognition as obtained by aptamer selection. Here, we will review the present knowledge on aptamers based on the G-4 structures and assess their diagnostic and therapeutic potential as biotech drugs for the detection and treatment of severe pathologies including vascular, cancer and viral diseases.
Mitochondrial Respiratory Complex I: Structure, Function and Implication in Human Diseases by Lokendra Sharma, Jianxin Lu, Yidong Bai (1266-1277).
Mitochondria are ubiquitous organelles in eukaryotic cells whose primary function is to generate energy supplies in the form of ATP through oxidative phosphorylation. As the entry point for most electrons into the respiratory chain, NADH:ubiquinone oxidoreductase, or complex I, is the largest and least understood component of the mitochondrial oxidative phosphorylation system. Substantial progress has been made in recent years in understanding its subunit composition, its assembly, the interaction among complex I and other respiratory components, and its role in oxidative stress and apoptosis. This review provides an updated overview of the structure of complex I, as well as its cellular functions, and discusses the implication of complex I dysfunction in various human diseases.
Iron Oxide Nanoparticle Platform for Biomedical Applications by J. Xie, J. Huang, X. Li, S. Sun, X. Chen (1278-1294).
Progress in nanosynthesis has succeeded in making nanoscale particles from iron oxide under precise quality control. Given the recent great advances in polymer manufacturing, antibody purification, DNA/RNA synthesis and magnetic resonance imaging (MRI), such iron oxide nanoparticles (IONPs) have been enriched with many variables and attracted great interest in studying their potential biomedical applications. After nearly two decades - effort, IONPs have become a powerful platform in many diverse aspects of biomedicine, including MRI, gene and drug delivery, and hyperthermia. While some studies are still at the proof-of-concept stage, others have now been widely used in clinics. With the on-going efforts to enhance their targeting ability and endow more functions, IONPs' future applications are highly expected.
Potential Applications of Hydrogen Sulfide-Induced Suspended Animation by Hamid Aslami, Marcus Schultz, Nicole Juffermans (1295-1303).
A suspended animation-like state has been induced in rodents with the use of hydrogen sulfide, resulting in hypothermia with a concomitant reduction in metabolic rate. Also oxygen demand was reduced, thereby protecting against hypoxia. Several therapeutic applications of induction of a hibernation-like state have been suggested, including ischemiareperfusion injury. More recently, hydrogen sulfide has been found to be protective in states of exaggerated inflammatory responses, such as acute lung injury. Possible mechanisms of this protective effect may include reduction of metabolism, as well as reduction of inflammation. In this manuscript, the methods of inducing a suspended animation-like state in experimental models using hydrogen sulfide are described. We discuss the effects of hydrogen sulfide-induced hypometabolism on hemodynamic, metabolic and inflammatory changes in animal models of various hypoxic and inflammatory diseases. In addition, potential therapeutic possibilities of hydrogen sulfide-induced hibernation are outlined.
Role of Copper in Angiogenesis and Its Medicinal Implications by Huiqi Xie, Y. Kang (1304-1314).
Copper promotion of angiogenesis has been known for more than two decades, but the mechanism of action of copper has not been explored until recently. Copper stimulation of factors involved in vessel formation and maturation, such as vascular endothelial growth factor (VEGF), is mainly responsible for its angiogenesis effect. Copper is required for the activation of hypoxia-inducible factor-1 (HIF-1), a major transcription factor regulating the expression of VEGF. Copper would be transported into nucleus by a copper chaperon for superoxide dismutase-1. Copper is required for HIF-1 interaction with the hypoxia-responsive element of the target genes and ensures the formation of HIF-1 transcriptional complex, thus activating the expression of target genes including VEGF. On the other hand, excess copper can stabilize HIF-1and#945;, the rate-limiting component of HIF-1, leading to its accumulation in cytoplasm and thus HIF-1 activation. The essential role of copper in production of VEGF makes it implicated in anti-angiogenesis therapy, such as the application of copper chelators in cancer therapy. However, suppression of angiogenesis is involved in the progression of heart hypertrophy and its transition to heart failure, therefore copper supplementation improves hypertrophic heart disease conditions. This dilemma of copper implications in cancer therapy and heart hypertrophy dictates a comprehensive understanding of a patient's condition before an implementation of copper manipulation therapy for different diseases. In this context, a development of diagnosis for copper metabolic changes as well as a tissue-specific copper manipulation would greatly benefit patients with an implication of copper manipulation therapy.