scholarly journals The P2′ residue is a key determinant of mesotrypsin specificity: engineering a high-affinity inhibitor with anticancer activity

2011 ◽  
Vol 440 (1) ◽  
pp. 95-105 ◽  
Author(s):  
Moh'd A. Salameh ◽  
Alexei S. Soares ◽  
Alexandra Hockla ◽  
Derek C. Radisky ◽  
Evette S. Radisky
Keyword(s):  
Cancer Cell ◽  
Therapeutic Potential ◽  
Tumour Progression ◽  
Trypsin Inhibitors ◽  
High Affinity ◽  
Kunitz Protease Inhibitor ◽  
Pancreatic Trypsin Inhibitor ◽  
Inhibitor Selectivity ◽  
Study Support ◽  
Clinical Potential

PRSS3/mesotrypsin is an atypical isoform of trypsin, the up-regulation of which has been implicated in promoting tumour progression. Mesotrypsin inhibitors could potentially provide valuable research tools and novel therapeutics, but small-molecule trypsin inhibitors have low affinity and little selectivity, whereas protein trypsin inhibitors bind poorly and are rapidly degraded by mesotrypsin. In the present study, we use mutagenesis of a mesotrypsin substrate, APPI (amyloid precursor protein Kunitz protease inhibitor domain), and of a poor mesotrypsin inhibitor, BPTI (bovine pancreatic trypsin inhibitor), to dissect mesotrypsin specificity at the key P2′ position. We find that bulky and charged residues strongly disfavour binding, whereas acidic residues facilitate catalysis. Crystal structures of mesotrypsin complexes with BPTI variants provide structural insights into mesotrypsin specificity and inhibition. Through optimization of the P1 and P2′ residues of BPTI, we generate a stable high-affinity mesotrypsin inhibitor with an equilibrium binding constant Ki of 5.9 nM, a >2000-fold improvement in affinity over native BPTI. Using this engineered inhibitor, we demonstrate the efficacy of pharmacological inhibition of mesotrypsin in assays of breast cancer cell malignant growth and pancreatic cancer cell invasion. Although further improvements in inhibitor selectivity will be important before clinical potential can be realized, the results of the present study support the feasibility of engineering protein protease inhibitors of mesotrypsin and highlight their therapeutic potential.

10-step Synthesis of 20-nor-Salvinorin A by Dynamic Strategic Bond Analysis

2017 ◽  
Author(s):  
Jeremy Roach ◽  
Yusuke Sasano ◽  
Cullen Schmid ◽  
Saheem Zaidi ◽  
Vsevolod Katritch ◽  
...  
Keyword(s):  
Total Synthesis ◽  
Opioid Receptors ◽  
Structural Modification ◽  
High Selectivity ◽  
Therapeutic Potential ◽  
Salvinorin A ◽  
High Affinity ◽  
Plant Metabolite ◽  
Complex Architecture ◽  
Property Modification

Salvinorin A (SalA) is a plant metabolite that agonizes the human <i>kappa</i>-opioid receptor (κ-OR) with high affinity and high selectivity over <i>mu- </i>and <i>delta-</i>opioid receptors. Its therapeutic potential has stimulated extensive semi-synthetic studies and total synthesis campaigns. However, structural modification of SalA has been complicated by its instability, and efficient total synthesis has been frustrated by its dense, complex architecture. Treatment of strategic bonds in SalA as dynamic and dependent on structural perturbation enabled the identification of an efficient retrosynthetic pathway. Here we show that deletion of C20 simultaneously stabilizes the SalA skeleton, simplifies its synthesis and retains its high affinity and selectivity for the κ-OR. The resulting 10-step synthesis now opens the SalA scaffold to deep-seated property modification.

Placental Therapy as Panacea: An Insight to Its Therapeutic Potential

2020 ◽  
Vol 06 ◽  
Author(s):  
Sayed Md Mumtaz ◽  
Madhu Gupta ◽  
Ramesh K. Goyal
Keyword(s):  
Tissue Regeneration ◽  
Therapeutic Potential ◽  
Biologically Active ◽  
Bioactive Components ◽  
Biochemical Mechanisms ◽  
Clinically Significant ◽  
Available Information ◽  
Clinical Potential ◽  
Placental Extract

Abstract:: The placenta that maintains and regulates the growth of fetus, consists of various biological treasures nutrients such as cytomedines, vitamins, trace elements, amino acids, peptides, growth factors and other biologically active constituents. Their therapeutic usefulness can well define in the terms of biochemical mechanisms of various components present in it. Biomedical waste derived extract is also a panacea for treatment of various diseases. Placental therapy has been reported specifically to have potent action on recovery of diseases and tissue regeneration. Placental bioactive components and their multi targeting identity prompted us to compile the précised information on placental extract products. However, some findings are needed to be explored by scientific community to prove their clinical potential with clinically significant statistical conclusions. In the light of available information and the usefulness of the placental extract, it is necessary for the development of various formulations for various unmet meet for the treatment as well as access their adverse effects as well as contradictions and precisely evaluated in the short and in the long-term periods.

scholarly journals P2X7 Receptor Promotes Mouse Mammary Cancer Cell Invasiveness and Tumour Progression, and Is a Target for Anticancer Treatment

Cancers ◽  
2020 ◽  
Vol 12 (9) ◽  
pp. 2342 ◽  
Author(s):  
Lucie Brisson ◽  
Stéphanie Chadet ◽  
Osbaldo Lopez-Charcas ◽  
Bilel Jelassi ◽  
David Ternant ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Cancer Cell ◽  
Cancer Progression ◽  
P2x7 Receptor ◽  
Mammary Cancer ◽  
Tumour Progression ◽  
Mammary Cancer Cell ◽  
Cell Invasiveness ◽  
Cancer Cell Invasiveness

The P2X7 receptor is an ATP-gated cation channel with a still ambiguous role in cancer progression, proposed to be either pro- or anti-cancerous, depending on the cancer or cell type in the tumour. Its role in mammary cancer progression is not yet defined. Here, we show that P2X7 receptor is functional in highly aggressive mammary cancer cells, and induces a change in cell morphology with fast F-actin reorganization and formation of filopodia, and promotes cancer cell invasiveness through both 2- and 3-dimensional extracellular matrices in vitro. Furthermore, P2X7 receptor sustains Cdc42 activity and the acquisition of a mesenchymal phenotype. In an immunocompetent mouse mammary cancer model, we reveal that the expression of P2X7 receptor in cancer cells, but not in the host mice, promotes tumour growth and metastasis development, which were reduced by treatment with specific P2X7 antagonists. Our results demonstrate that P2X7 receptor drives mammary tumour progression and represents a pertinent target for mammary cancer treatment.

scholarly journals The regio-selective synthesis of 10-hydroxy camptothecin norcantharidin conjugates and their biological activity evaluation in vitro

2018 ◽  
Vol 5 (6) ◽  
pp. 172317 ◽  
Author(s):  
Chang K. Zhao ◽  
Chan Li ◽  
Xian H. Wang ◽  
Yu J. Bao ◽  
Fu H. Yang ◽  
...  
Keyword(s):  
Biological Activity ◽  
Cell Growth ◽  
Cancer Treatment ◽  
Cancer Cell ◽  
Therapeutic Potential ◽  
Selective Synthesis ◽  
Cancer Cell Growth ◽  
Activity Evaluation ◽  
Moderate Yield

A series of conjugates of 10-hydroxy camptothecin (HCPT) with functionalized norcantharidin derivatives were regio-selectively synthesized in the condition of (3-dimethylaminopropyl) ethyl-carbodiimide monohydrochloride in a moderate yield. The synthesized conjugate HCPT pro-drugs can also suppress cancer cell growth in vitro . These conjugated pro-drug constructs possess therapeutic potential as novel bi-functional conjugate platforms for cancer treatment.

scholarly journals Redox Modulation at Work: Natural Phytoprotective Polysulfanes From Alliums Based on Redox-Active Sulfur

2018 ◽  
Vol 4 (5) ◽  
pp. 397-407 ◽  
Author(s):  
Awais Anwar ◽  
Emma Gould ◽  
Ryan Tinson ◽  
Javaid Iqbal ◽  
Chris Hamilton
Keyword(s):  
Cell Lines ◽  
Cancer Cell ◽  
Therapeutic Potential ◽  
Antimicrobial Properties ◽  
Molecular Targets ◽  
Cancer Cell Lines ◽  
Special Focus ◽  
Anticancer Activities ◽  
Comprehensive Overview ◽  
Anticancer Properties

Abstract Purpose of review This article provides a brief overview of natural phytoprotective products of allium with a special focus on the therapeutic potential of diallyl polysulfanes from garlic, their molecular targets and their fate in the living organisms. A comprehensive overview of antimicrobial and anticancer properties of published literature is presented for the reader to understand the effective concentrations of polysulfanes and their sensitivity towards different human pathogenic microbes, fungi, and cancer cell lines. Recent findings The article finds polysulfanes potentials as new generation novel antibiotics and chemo preventive agent. The effective dose rates of polysulfanes for antimicrobial properties are in the range of 0.5–40 mg/L and for anticancer 20–100 μM. The molecular targets for these redox modulators are mainly cellular thiols as well as inhibition and/or activation of certain cellular proteins in cancer cell lines. Summary Antimicrobial and anticancer activities of polysulfanes published in the literature indicate that with further development, they could be promising candidates for cancer prevention due to their selectivity towards abnormal cells.

scholarly journals Reduced expression of ΔΝp63α in cervical squamous cell carcinoma

2011 ◽  
Vol 34 (3) ◽  
pp. 184 ◽  
Author(s):  
Ying Zhou ◽  
Qianqian Xu ◽  
Bin Ling ◽  
Weihua Xiao ◽  
Peishu Liu
Keyword(s):  
Cell Lines ◽  
Cancer Cell ◽  
Squamous Cell ◽  
Squamous Cell Cancer ◽  
Tumour Progression ◽  
Cell Cancer ◽  
Cancer Tissue ◽  
P53 Family ◽  
Squamous Cancer ◽  
Cervical Squamous Cancer

Purpose: As a member of the p53 family, p63 is considered to be an important differentiation regulation transcriptional factor, but the roles of p63 in many epithelial tumourigenesis and metastasis processes are still not clear. This study was designed to investigate the expression of p63 and its isoform in normal tissues and squamous cell cancer tissues of uterine cervix, and its significance in cancer cell differentiation. Methods: The expression of p63 was assessed in cervical tissue and cell lines by immunohistochemistry, RT-PCR and Western Blotting. The relationships between p63 protein, various clinico-pathological features, and the differentiation marker involucrin were analyzed. Results: ΔΝp63α is the predominant isoform expressed in cervical epithelial tissues, and it is decreased in moderately or poorly differentiated cervical squamous carcinoma, as well as in the HeLa, SiHa and C33A cervical cancer cell lines. The expression level of ΔΝp63α was positively correlated with that of involucrin in cervical squamous cancer tissue, and the expression of ΔΝp63α is decreased with the degree of tumour invasion. Conclusion: The decrease of ΔΝp63α in cervical squamous cell cancer appears to be associated with the tumour progression, and ΔΝp63α may be a sensitive marker for cervical squamous cancer differentiation.

scholarly journals The Multi-Functional Calcium/Calmodulin Stimulated Protein Kinase (CaMK) Family: Emerging Targets for Anti-Cancer Therapeutic Intervention

2019 ◽  
Vol 12 (1) ◽  
pp. 8 ◽  
Author(s):  
Joshua S. Brzozowski ◽  
Kathryn A. Skelding
Keyword(s):  
Protein Kinase ◽  
Cancer Cell ◽  
Therapeutic Intervention ◽  
Cell Function ◽  
Tumour Progression ◽  
Anti Cancer ◽  
Signalling Cascades ◽  
Key Events

The importance of Ca2+ signalling in key events of cancer cell function and tumour progression, such as proliferation, migration, invasion and survival, has recently begun to be appreciated. Many cellular Ca2+-stimulated signalling cascades utilise the intermediate, calmodulin (CaM). The Ca2+/CaM complex binds and activates a variety of enzymes, including members of the multifunctional Ca2+/calmodulin-stimulated protein kinase (CaMK) family. These enzymes control a broad range of cancer-related functions in a multitude of tumour types. Herein, we explore the cancer-related functions of these kinases and discuss their potential as targets for therapeutic intervention.

scholarly journals The Role of Simvastatin in the Therapeutic Approach of Rheumatoid Arthritis

2013 ◽  
Vol 2013 ◽  
pp. 1-7 ◽  
Author(s):  
Lucia Cojocaru ◽  
Andrei Constantin Rusali ◽  
Cristina Şuţa ◽  
Anca Mihaela Rădulescu ◽  
Maria Şuţa ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Cardiovascular Disease ◽  
Active Rheumatoid Arthritis ◽  
Therapeutic Potential ◽  
Efficacy And Safety ◽  
Good Safety Profile ◽  
Study Support ◽  
Anti Inflammatory ◽  
Inflammatory Effect

The pleiotropic effects of statins, especially the anti-inflammatory and immunomodulatory ones, indicate that their therapeutic potential might extend beyond cholesterol lowering and cardiovascular disease to other inflammatory disorders such as rheumatoid arthritis. Therefore, we undertook a prospective cohort study to evaluate the efficacy and safety of simvastatin used for inflammation control in patients with rheumatoid arthritis. One hundred patients with active rheumatoid arthritis divided into two equal groups (the study one who received 20 mg/day of simvastatin in addition to prior DMARDs and the control one) were followed up over six months during three study visits. The results of the study support the fact that simvastatin at a dose of 20 mg/day has a low anti-inflammatory effect in patients with rheumatoid arthritis with a good safety profile.

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