Thioredoxin Reductase and its Inhibitors

Author(s):

Fulvio Saccoccia, Francesco Angelucci, Giovanna Boumis, Daniela Carotti, Gianni Desiato, Adriana E. Miele and Andrea BellelliPages 621-646 (26)

Abstract:

Thioredoxin plays a crucial role in a wide number of physiological processes, which span from reduction of nucleotides to deoxyriboucleotides to the detoxification from xenobiotics, oxidants and radicals. The redox function of Thioredoxin is critically dependent on the enzyme Thioredoxin NADPH Reductase (TrxR). In view of its indirect involvement in the above mentioned physio/pathological processes, inhibition of TrxR is an important clinical goal. As a general rule, the affinities and mechanisms of binding of TrxR inhibitors to the target enzyme are known with scarce precision and conflicting results abound in the literature. A relevant analysis of published results as well as the experimental procedures is therefore needed, also in view of the critical interest of TrxR inhibitors. We review the inhibitors of TrxR and related flavoreductases and the classical treatment of reversible, competitive, non competitive and uncompetitive inhibition with respect to TrxR, and in some cases we are able to reconcile contradictory results generated by oversimplified data analysis.

Keywords:

Thioredoxin reductase, mechanism of inhibition, competitive inhibitor, uncompetitive inhibitor, irreversible inhibitor, suicide substrates, pseudo-irreversible inhibition, double-substrate enzyme.

Affiliation:

Istituto Pasteur – Fondazione Cenci-Bolognetti, Istituto di Biologia e Medicina Molecolare del CNR, Dipartimento di Scienze Biochimiche “A. Rossi Fanelli”, Sapienza Università di Roma, Piazzale A. Moro 5, 00185 Rome, Italy.

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Disintegrins from Snake Venoms and their Applications in Cancer Research and Therapy

Author(s):

Jessica Kele Arruda Macedo, Jay W. Fox and Mariana de Souza CastroPages 532-548 (17)

Abstract:

Integrins regulate diverse functions in cancer pathology and in tumor cell development and contribute to important processes such as cell shape, survival, proliferation, transcription, angiogenesis, migration, and invasion. A number of snake venom proteins have the ability to interact with integrins. Among these are the disintegrins, a family of small, non-enzymatic, and cysteine-rich proteins found in the venom of numerous snake families. The venom proteins may have a potential role in terms of novel therapeutic leads for cancer treatment. Disintegrin can target specific integrins and as such it is conceivable that they could interfere in important processes involved in carcinogenesis, tumor growth, invasion and migration. Herein we present a survey of studies involving the use of snake venom disintegrins for cancer detection and treatment. The aim of this review is to highlight the relationship of integrins with cancer and to present examples as to how certain disintegrins can detect and affect biological processes related to cancer. This in turn will illustrate the great potential of these molecules for cancer research. Furthermore, we also outline several new approaches being created to address problems commonly associated with the clinical application of peptide-based drugs such as instability, immunogenicity, and availability.

Keywords:

Antitumor, carcinogenesis, cell death, integrins, metastasis, snake venoms, tumor promotion.

Affiliation:

Department of Microbiology, Immunology and Cancer Biology, University of Virginia School of Medicine, USA.

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Targeting EZH2 for Cancer Therapy: Progress and Perspective

Author(s):

Chi Han Li and Yangchao ChenPages 559-570 (12)

Abstract:

Enhancer of Zeste Homolog 2 (EZH2) is the core component of the polycomb repressive complex 2 (PRC2), possessing the enzymatic activity in generating di/tri-methylated lysine 27 in histone H3. EZH2 has important roles during early development, and its dysregulation is heavily linked to oncogenesis in various tissue types. Accumulating evidences suggest a remarkable therapeutic potential by targeting EZH2 in cancer cells. The first part reviews current strategies to target EZH2 in cancers, and evaluates the available compounds and agents used to disrupt EZH2 functions. Then we provide insight to the future direction of the research on targeting EZH2 in different cancer types. We comprehensively discuss the current understandings of the 1) structure and biological activity of EZH2, 2) its role during the assembling of PRC2 and recruitment of other protein components, 3) the molecular events directing EZH2 to target genomic regions, and 4) post-translational modification at EZH2 protein. The discussion provides the basis to inspire the development of novel strategies to abolish EZH2-related effects in cancer cells.

Keywords:

Chemotherapy, DNA methylation, DZNep, EZH2, H3K27me3, LncRNA, PRC2, SET domain.

Affiliation:

School of Biomedical Sciences, Faculty of Medicine, the Chinese University of Hong Kong, Shatin, NT, Hong Kong.

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Mutations of Chromatin Structure Regulating Genes in Human Malignancies

Author(s):

Jian Chen, Franklin H. Herlong, John R. Stroehlein and Lopa MishraPages 411-437 (27)

Abstract:

Chromatin structure regulating processes mediated by the adenosine triphosphate (ATP) – dependent chromatin remodeling complex and the covalent histone-modifying complexes are critical to gene transcriptional control and normal cellular processes, including cell stemness, differentiation, and proliferation. Gene mutations, structural abnormalities, and epigenetic modifications that lead to aberrant expression of chromatin structure regulating members have been observed in most of human malignancies. Advances in next-generation sequencing (NGS) technologies in recent years have allowed in-depth study of somatic mutations in human cancer samples. The Cancer Genome Atlas (TCGA) is the largest effort to date to characterize cancer genome using NGS technology. In this review, we summarize somatic mutations of chromatin-structure regulating genes from TCGA publications and other cancer genome studies, providing an overview of genomic alterations of chromatin regulating genes in human malignancies.

Keywords:

Somatic mutation, Cancer, Chromatin structure, Chromatin remodeling, Chromatin modification, TCGA.

Affiliation:

Department of Gastroenterology, Hepatology and Nutrition, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.

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The Melanocortin Receptor System: A Target for Multiple Degenerative Diseases

Author(s):

Minying Cai and Victor J. HrubyPages 488-496 (9)

Abstract:

The melanocortin receptor system consists of five closely related G-protein coupled receptors (MC1R, MC2R, MC3R, MC4R and MC5R). These receptors are involved in many of the key biological functions for multicellular animals, including human beings. The natural agonist ligands for these receptors are derived by processing of a primordial animal gene product, proopiomelanocortin (POMC). The ligand for the MC2R is ACTH (Adrenal Corticotropic Hormone), a larger processed peptide from POMC. The natural ligands for the other 4 melanocortin receptors are smaller peptides including α-melanocyte stimulating hormone (α-MSH) and related peptides from POMC (β-MSH and γ-MSH). They all contain the sequence His-Phe-Arg-Trp that is conserved throughout evolution. Thus, there has been considerable difficulty in developing highly selective ligands for the MC1R, MC3R, MC4R and MC5R. In this brief review, we discuss the various approaches that have been taken to design agonist and antagonist analogues and derivatives of the POMC peptides that are selective for the MC1R, MC3R, MC4R and MC5R receptors, via peptide, nonpeptide and peptidomimetic derivatives and analogues and their differential interactions with receptors that may help account for these selectivities.

Keywords:

Melanocortin Receptors (MCRs: MC1R, MC2R, MC3R, MC4R, MC5R); α-MSH: α -melanocyte stimulate hormone; POMC: Proopiomelanocortin; ACTH: adrenal corticotropic hormone; GPCRs: G-protein coupled receptors; ASIP: agouti signaling protein; AGRP: agouti related protein; MTI: Ac-Ser-Tyr-Ser-Met-Glu-His-DPhe-Arg-Trp-Gly-Lys-Pro-Val- NH2; MT-II: Ac-Nle4-c[Asp5, D-Phe7, Lys10]α-MSH(4-10)-NH2, (Ac-Nle-c[Asp-His-DPhe-Arg-Trp-Lys]-NH2). SHU9119: Ac- Nle4-c[Asp5, D-Nal(2’)7, Lys10]α-MSH(4-10)-NH2, (Ac-Nle-c[Asp-His- D-Nal(2’)-Arg-Trp-Lys]-NH2).

Affiliation:

Department of Chemistry & Biochemistry, University of Arizona, 1306 E. University Blvd, Tucson, AZ 85721, USA.

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