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Anticancer Therapeutics (anticancer + therapeutics)

Distribution by Scientific Domains

Chemistry	75%

Selected Abstracts

Role of metalloproteins in the clinical management of head and neck squamous cell carcinoma

HEAD & NECK: JOURNAL FOR THE SCIENCES & SPECIALTIES OF THE HEAD AND NECK, Issue 12 2007
W. Cooper Scurry Jr. MD
Abstract Metalloproteins are a group of catalytic proteins, which play significant roles in cell cycle and death. Matrix metalloproteinases (MMPs) are a family of endopeptidases that are capable of digesting extracellular matrix components. They have been implicated in carcinogenesis and recent developments have been made to use MMPs clinically to predict outcomes. In the future, selective inhibition of these proteins and their regulatory pathways may prove useful in anticancer therapeutics. We present a review article on the clinical applications of metalloproteins in head and neck squamous cell carcinoma (HNSCC). Metalopanstimulin is highlighted as a putative metalloprotein of interest for those treating HNSCC. Expression of particular metalloproteins has correlation with lymph node metastasis, tumor invasiveness, and overall prognosis in HNSCC. © 2007 Wiley Periodicals, Inc. Head Neck 2007 [source]

Listeriolysin O as cytotoxic component of an immunotoxin

PROTEIN SCIENCE, Issue 6 2009
Sabine Bergelt
Abstract Monoclonal antibodies (mAbs) have been developed over the past years as promising anticancer therapeutics. The conjugation of tumor specific mAbs with cytotoxic molecules has been shown to improve their efficacy dramatically. These bifunctional immunotoxins, consisting of covalently linked antibodies and protein toxins, possess considerable potential in cancer therapy. Many of them are under investigation in clinical trials. As a result of general interest in new toxic components, we describe here the suitability of the bacterial protein Listeriolysin O (LLO) as cytotoxic component of an immunotoxin. Unique characteristics of LLO, such as its acidic pH optimum and the possibility to regulate the cytolytic activity by cysteine-oxidation, make LLO an interesting toxophore. Oxidized LLO shows a substantially decreased cytolytic activity when compared with the reduced protein as analyzed by hemolysis. Both oxidized and reduced LLO exhibit a cell-type-unspecific toxicity in cell culture with a significantly higher toxicity of reduced LLO. For cell-type-specific targeting of LLO to tumor cells, LLO was coupled to the dsFv fragment of the monoclonal antibody B3, which recognizes the tumor-antigen Lewis Y. The coupling of LLO to dsFv-B3 was performed via cysteine-containing polyionic fusion peptides that act as a specific heterodimerization motif. The novel immunotoxin B3-LLO could be shown to specifically eliminate antigen positive MCF7 cells with an EC50 value of 2.3 nM, whereas antigen negative cell lines were 80- to 250-fold less sensitive towards B3-LLO. [source]

Proteomic and transcriptomic study on the action of a cytotoxic saponin (Polyphyllin D): Induction of endoplasmic reticulum stress and mitochondria-mediated apoptotic pathways

PROTEINS: STRUCTURE, FUNCTION AND BIOINFORMATICS, Issue 15 2008
Fung-Ming Siu
Abstract Polyphyllin D (PD) is a potent cytotoxic saponin found in Paris polyphylla. In the present study, bioinformatic, proteomic and transcriptomic analyses were performed to study the mechanisms of action of PD on human nonsmall cell lung cancer (NSCLC) cell line (NCI-H460). Using a gene expression-based bioinformatic tool (connectivity map), PD was identified as a potential ER stress inducer. Our proteomic and transcriptomic analyses revealed that PD treatment led to upregulation of typical ER stress-related proteins/genes including glucose-regulated protein 78 (BiP/GRP78) and protein disulfide isomerase (PDI). In particular, elevated expression of C/EBP homologous transcription factor (chop) and activation of caspase-4 occurred at early time point (8,h) of PD treatment, signifying an initial ER stress-mediated apoptosis. Induction of tumor suppressor p53, disruption of mitochondrial membrane, activation of caspase-9 and caspase-3 were detected upon prolonged PD treatment. Collectively, these data revealed that PD induced the cytotoxic effect through a mechanism initiated by ER stress followed by mitochondrial apoptotic pathway. The ability of activating two major pathways of apoptosis makes PD an attractive drug lead for anticancer therapeutics. [source]

Structures of the wild-type and activated catalytic domains of Brachydanio rerio Polo-like kinase 1 (Plk1): changes in the active-site conformation and interactions with ligands

ACTA CRYSTALLOGRAPHICA SECTION D, Issue 9 2008
Robert A. Elling
Polo-like kinase 1 (Plk1) is a member of a family of serine/threonine kinases involved in the regulation of cell-cycle progression and cytokinesis and is an attractive target for the development of anticancer therapeutics. A zebrafish homolog of the human Plk1 (hPlk1) kinase domain (KD) was identified that can be expressed in large quantities in bacteria and crystallizes readily, whether in a wild-type form or as a variant containing the activating Thr196,Asp substitution, in one space group and under similar conditions both in the absence and presence of active-site compounds. This construct was validated by testing a panel of hPlk1 inhibitors against human and zebrafish proteins and it was shown that the selected small molecules inhibited the homologs with a high degree of correlation. Crystal structures of ligand-free wild-type and activated zebrafish Plk1 (zPlk1) KDs revealed the organization of the secondary structural elements around the active site and demonstrated that the activation segment was disordered in the activated form of the domain but possessed a well defined secondary structure in the wild-type enzyme. The cocrystal structure of wild-type zPlk1 KD with ADP documented the hydrolysis of ATP and revealed the phosphorylation site. The cocrystal structure of the activated KD with wortmannin, a covalent inhibitor of Plk1 and PI3 kinases, showed the binding mode of the small molecule to the enzyme and may facilitate the design of more potent Plk1 inhibitors. The work presented in this study establishes the zPlk1 KD as a useful tool for rapid low- and high-throughput structure-based screening and drug discovery of compounds specific for this mitotic target. [source]