scholarly journals Molecular targets in cancer therapy: the Ron approach

2011 ◽  
pp. 215-224
Author(s):  
Serena Germano ◽  
Giovanni Gaudino
Keyword(s):  
Receptor Tyrosine Kinase ◽  
Molecular Targets ◽  
Clinical Intervention ◽  
Positive Association ◽  
Biological Indicators ◽  
Receptor Activation ◽  
Macrophage Stimulating Protein ◽  
Epithelial Cancers ◽  
Multiple Processes

The receptor tyrosine kinase Ron and its ligand, Macrophage Stimulating Protein (MSP), mediate multiple processes involved in the control of cell proliferation, migration and protection from apoptosis. Dysregulated signaling of Ron, due to hyperactivation or loss of negative regulation, is involved in tumor progression and metastasis. Growing evidence indicates that Ron is abnormally expressed and activated in certain types of primary epithelial cancers (i.e. breast, colon, lung, pancreas, bladder and thyroid), where it critically contributes to the maintenance of tumorigenic and invasive phenotype. Furthermore, a positive association between aberrant Ron expression and aggressive biological indicators as well as a worse clinical outcome have been reported in breast, bladder and thyroid carcinomas. Different approaches have proved effective in targeting receptor activation/expression both in vitro and in animal models, leading to reversion of the tumorigenic phenotype. Altogether these results show that Ron is an attractive molecular target for clinical intervention.

The Predominant microRNAs in β-cell Clusters for Insulin Regulation and Diabetic Control

2020 ◽  
Vol 21 (7) ◽  
pp. 722-734
Author(s):  
Adele Soltani ◽  
Arefeh Jafarian ◽  
Abdolamir Allameh
Keyword(s):  
Mirna Expression ◽  
Expression Profiles ◽  
Expression Patterns ◽  
Diabetic Control ◽  
In Vitro Proliferation ◽  
Cell Functions ◽  
Mirna Expression Profiles ◽  
Multiple Processes ◽  
The Impact

micro (mi)-RNAs are vital regulators of multiple processes including insulin signaling pathways and glucose metabolism. Pancreatic β-cells function is dependent on some miRNAs and their target mRNA, which together form a complex regulative network. Several miRNAs are known to be directly involved in β-cells functions such as insulin expression and secretion. These small RNAs may also play significant roles in the fate of β-cells such as proliferation, differentiation, survival and apoptosis. Among the miRNAs, miR-7, miR-9, miR-375, miR-130 and miR-124 are of particular interest due to being highly expressed in these cells. Under diabetic conditions, although no specific miRNA profile has been noticed, the expression of some miRNAs and their target mRNAs are altered by posttranscriptional mechanisms, exerting diverse signs in the pathobiology of various diabetic complications. The aim of this review article is to discuss miRNAs involved in the process of stem cells differentiation into β-cells, resulting in enhanced β-cell functions with respect to diabetic disorders. This paper will also look into the impact of miRNA expression patterns on in vitro proliferation and differentiation of β-cells. The efficacy of the computational genomics and biochemical analysis to link the changes in miRNA expression profiles of stem cell-derived β-cells to therapeutically relevant outputs will be discussed as well.

Hepatocyte Growth Factor and Macrophage-stimulating Protein “Hinge” Analogs to Treat Pancreatic Cancer

2019 ◽  
Vol 19 (10) ◽  
pp. 782-795
Author(s):  
John W. Wright ◽  
Kevin J. Church ◽  
Joseph W. Harding
Keyword(s):  
Pancreatic Cancer ◽  
Signal Transduction ◽  
Growth Factor ◽  
Hepatocyte Growth Factor ◽  
Tumor Growth ◽  
Receptor Activation ◽  
Signal Transduction Pathways ◽  
Met Receptor ◽  
Macrophage Stimulating Protein ◽  
Hepatocyte Growth

Pancreatic cancer (PC) ranks twelfth in frequency of diagnosis but is the fourth leading cause of cancer related deaths with a 5 year survival rate of less than 7 percent. This poor prognosis occurs because the early stages of PC are often asymptomatic. Over-expression of several growth factors, most notably vascular endothelial growth factor (VEGF), has been implicated in PC resulting in dysfunctional signal transduction pathways and the facilitation of tumor growth, invasion and metastasis. Hepatocyte growth factor (HGF) acts via the Met receptor and has also received research attention with ongoing efforts to develop treatments to block the Met receptor and its signal transduction pathways. Macrophage-stimulating protein (MSP), and its receptor Ron, is also recognized as important in the etiology of PC but is less well studied. Although the angiotensin II (AngII)/AT1 receptor system is best known for mediating blood pressure and body water/electrolyte balance, it also facilitates tumor vascularization and growth by stimulating the expression of VEGF. A metabolite of AngII, angiotensin IV (AngIV) has sequence homology with the “hinge regions” of HGF and MSP, key structures in the growth factor dimerization processes necessary for Met and Ron receptor activation. We have developed AngIV-based analogs designed to block dimerization of HGF and MSP and thus receptor activation. Norleual has shown promise as tested utilizing PC cell cultures. Results indicate that cell migration, invasion, and pro-survival functions were suppressed by this analog and tumor growth was significantly inhibited in an orthotopic PC mouse model.

Discovery of Novel 2-Amino-5-(Substituted)-1,3,4-Thiadiazole Derivatives: New Utilities for Colon Cancer Treatment

2018 ◽  
Vol 18 (5) ◽  
pp. 719-738 ◽  
Author(s):  
Vinit Raj ◽  
Amit Rai ◽  
Ashok K. Singh ◽  
Amit K. Keshari ◽  
Prakruti Trivedi ◽  
...  
Keyword(s):  
Colon Cancer ◽  
Cancer Metastasis ◽  
Molecular Targets ◽  
Cancer Cell Line ◽  
Chemotherapeutic Agents ◽  
Cancer Drug ◽  
Human Colon Cancer ◽  
Thiadiazole Derivatives ◽  
Ht 29

Background: Colon cancer is one of the most widespread disease, the mortality rate is high due to cancer metastasis and the development of drug resistance. In this regards, new chemotherapeutic agents with specific mechanisms of action and significant effect on patient’s survival are the new era for the colon cancer drug development. Objective: The main objective of present study was to design, synthesize of a novel series of 1,3,4-thiadiazole derivatives (VR1 to VR35) and screen them against HT-29 human colon cancer cell line. Method: Newly 1,3,4-thiadiazole scaffold were designed, synthesized and further, characterized by FTIR, NMR (1H and 13C), MS and elemental analyses. Before the synthesis, molecular dynamic simulation and ADME studies were performed to find out the most potent lead compounds. Later, SRB assay using HT-29 cells and ELISA assays were performed to explore activity and molecular targets of VR24 and VR27 and find out whether in silico data had a similar pattern in the molecular level. Results: The results of docking study revealed that both VR24 and VR27 had interaction energy >-5 kcal/mol with various assigned molecular targets and the ligand-protein complexes were found to be stable with IL-6. The computational analysis of molecules showed good ADMET profiling. Later, the in vitro anticancer study was conducted where VR24 and VR27 were found to be active against HT-29 cells (GI50<10 µM). Finally, ELISA assays revealed that both the compounds had higher inhibition properties to various biomarker of colon cancer like IL-6 and COX-2. Conclusion: Collectively, these result suggested that VR24 and VR27 inhibited the assigned molecular targets, imparting their ameliorative effects against colon cancer. Due to these encouraging results, we concluded that both VR24 and VR27 may be effective against colon cancer therapy in future.

scholarly journals Targeting RON receptor tyrosine kinase for treatment of advanced solid cancers: antibody–drug conjugates as lead drug candidates for clinical trials

2020 ◽  
Vol 12 ◽  
pp. 175883592092006
Author(s):  
Hang-Ping Yao ◽  
Sreedhar Reddy Suthe ◽  
Xiang-Min Tong ◽  
Ming-Hai Wang
Keyword(s):  
Clinical Trials ◽  
Tyrosine Kinase ◽  
Receptor Tyrosine Kinase ◽  
Targeted Therapeutics ◽  
Antibody Drug Conjugates ◽  
Drug Candidates ◽  
Drug Conjugates ◽  
Ron Receptor ◽  
Antibody Drug

The recepteur d’origine nantais (RON) receptor tyrosine kinase, belonging to the mesenchymal-to-epithelial transition proto-oncogene family, has been implicated in the pathogenesis of cancers derived from the colon, lung, breast, and pancreas. These findings lay the foundation for targeting RON for cancer treatment. However, development of RON-targeted therapeutics has not gained sufficient attention for the last decade. Although therapeutic monoclonal antibodies (TMABs) targeting RON have been validated in preclinical studies, results from clinical trials have met with limited success. This outcome diminishes pharmaceutical enthusiasm for further development of RON-targeted therapeutics. Recently, antibody–drug conjugates (ADCs) targeting RON have drawn special attention owing to their increased therapeutic activity. The rationale for developing anti-RON ADCs is based on the observation that cancer cells are not sufficiently addicted to RON signaling for survival. Thus, TMAB-mediated inhibition of RON signaling is ineffective for clinical application. In contrast, anti-RON ADCs combine a target-specific antibody with potent cytotoxins for cancer cell killing. This approach not only overcomes the shortcomings in TMAB-targeted therapies but also holds the promise for advancing anti-RON ADCs into clinical trials. In this review, we discuss the latest advancements in the development of anti-RON ADCs for targeted cancer therapy including drug conjugation profile, pharmacokinetic properties, cytotoxic effect in vitro, efficacy in tumor models, and toxicological activities in primates.

scholarly journals In Vitro Chemopreventive Potential of Phlorotannins-Rich Extract from Brown Algae by Inhibition of Benzo[a]pyrene-Induced P2X7 Activation and Toxic Effects

Marine Drugs ◽  
2021 ◽  
Vol 19 (1) ◽  
pp. 34
Author(s):  
Mélody Dutot ◽  
Elodie Olivier ◽  
Sophie Fouyet ◽  
Romain Magny ◽  
Karim Hammad ◽  
...  
Keyword(s):  
Brown Algae ◽  
P2x7 Receptor ◽  
Biological Activities ◽  
Receptor Activation ◽  
Cytotoxic Effects ◽  
Human Lung Cells ◽  
Cytochrome P450 Activity ◽  
Species Production ◽  
E Cadherin

Phlorotannins are polyphenols occurring exclusively in some species of brown algae, known for numerous biological activities, e.g., antioxidant, antiproliferative, antidiabetic, and antiallergic properties. Their effects on the response of human lung cells to benzo[a]pyrene (B[a]P) has not been characterized. Our objective was to in vitro evaluate the effects of a phlorotannin-rich extract obtained from the brown algae Ascophyllum nodosum and Fucus vesiculosus on B[a]P cytotoxic effects. The A549 cell line was incubated with B[a]P for 48 and 72 h in the presence or absence of the brown algae extract. Cytochrome P450 activity, activation of P2X7 receptor, F-actin disorganization, and loss of E-cadherin expression were assessed using microplate cytometry and fluorescence microscopy. Relative to control, incubation with the brown algae extract was associated with lower B[a]P-induced CYP1 activity, lower P2X7 receptor activation, and lower reactive oxygen species production. The brown algae extract inhibited the alterations of F-actin arrangement and the downregulation of E-cadherin expression. We identified a phlorotannins-rich extract that could be deeper investigated as a cancer chemopreventive agent to block B[a]P-mediated carcinogenesis.

scholarly journals Network pharmacology-based analysis for unraveling potential cancer-related molecular targets of Egyptian propolis phytoconstituents accompanied with molecular docking and in vitro studies

RSC Advances ◽  
2021 ◽  
Vol 11 (19) ◽  
pp. 11610-11626
Author(s):  
Reham S. Ibrahim ◽  
Alaa A. El-Banna
Keyword(s):  
Molecular Docking ◽  
Cancer Treatment ◽  
Mechanism Of Action ◽  
Molecular Targets ◽  
Integrated Approach ◽  
In Vitro Studies ◽  
Network Pharmacology ◽  
Multi Level ◽  
Potential Cancer

Multi-level mechanism of action of propolis constituents in cancer treatment using an integrated approach of network pharmacology-based analysis, molecular docking and in vitro cytotoxicity testing.

Mu-opioid receptor activation promotes in vitro and in vivo tumor growth in head and neck squamous cell carcinoma

Life Sciences ◽  
2021 ◽  
Vol 278 ◽  
pp. 119541
Author(s):  
Aysegul Gorur ◽  
Miguel Patiño ◽  
Hideaki Takahashi ◽  
German Corrales ◽  
Curtis R. Pickering ◽  
...  
Keyword(s):  
Squamous Cell Carcinoma ◽  
Tumor Growth ◽  
Cell Carcinoma ◽  
Head And Neck ◽  
Opioid Receptor ◽  
Receptor Activation ◽  
Mu Opioid Receptor ◽  
Mu Opioid

scholarly journals Point-Substitution of Phenylalanine Residues of 26RFa Neuropeptide: A Structure-Activity Relationship Study

Molecules ◽  
2021 ◽  
Vol 26 (14) ◽  
pp. 4312
Author(s):  
Benjamin Lefranc ◽  
Karima Alim ◽  
Cindy Neveu ◽  
Olivier Le Marec ◽  
Christophe Dubessy ◽  
...  
Keyword(s):  
Receptor Activation ◽  
Pharmacological Profile ◽  
Acid Moiety ◽  
Structural Determinants ◽  
Physiological Processes ◽  
Structure Activity ◽  
Peptide Derivatives ◽  
Targeting Peptide ◽  
G Protein Coupled

26RFa is a neuropeptide that activates the rhodopsin-like G protein-coupled receptor QRFPR/GPR103. This peptidergic system is involved in the regulation of a wide array of physiological processes including feeding behavior and glucose homeostasis. Herein, the pharmacological profile of a homogenous library of QRFPR-targeting peptide derivatives was investigated in vitro on human QRFPR-transfected cells with the aim to provide possible insights into the structural determinants of the Phe residues to govern receptor activation. Our work advocates to include in next generations of 26RFa(20–26)-based QRFPR agonists effective substitutions for each Phe unit, i.e., replacement of the Phe22 residue by a constrained 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid moiety, and substitution of both Phe24 and Phe26 by their para-chloro counterpart. Taken as a whole, this study emphasizes that optimized modifications in the C-terminal part of 26RFa are mandatory to design selective and potent peptide agonists for human QRFPR.

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