Abstract
Neurotrophins (NTs) and their receptors, TrKs and p75NTR, have been shown to regulate proliferation and apoptosis of neoplastic cells. Pharmacological TrK blockade is considered a valuable target in cancer therapy, and several TrK inhibitors are under investigation. However, only a few of them have reached the stage of clinical development. Myosarcomas are aggressive cancers, which secrete NGF and respond poorly to available chemotherapies. Our previous work has shown that these cancers, characterized by autocrine activation of TrKA by NGF, which promotes cancer growth and survival, are highly susceptible to TrK blockade, both in vitro and in vivo. The same pattern has also been described in prostatic carcinoma. The present report characterizes for the first time the anti-proliferative and pro-apoptotic effects of the oxindole TrK inhibitor GW441756, in a panel of human myosarcomas and prostatic adenocarcinoma cell lines. Furthermore, we provide novel evidence that, in myosarcomas, characterized by a high-TrK/low-p75NTR phenotype, GW441756 upregulates p75NTR receptor expression, leading to apoptosis via caspase-3 activation. Altogether, our data expand the knowledge of the anti-neoplastic and pro-apoptotic mechanisms of GW441756, and of TrK inhibitors in general, lending further support to the therapeutic potential of TrK blockade in clinical oncology.
Keywords: Apoptosis, Cancer, GW441756, Neurotrophins, p75NTR, myosarcoma, TrKs, Trk inhibitors
Current Signal Transduction Therapy
Title:Antiproliferative and Proapoptotic Effects of the TrK-inhibitor GW441756 in Human Myosarcomas and Prostatic Carcinoma
Volume: 8 Issue: 1
Author(s): Anna M. Stabile, Claudia Montagnoli, Alessandra Pistilli, Maria Grazia Rambotti, Grazia Pula and Mario Rende
Affiliation:
Keywords: Apoptosis, Cancer, GW441756, Neurotrophins, p75NTR, myosarcoma, TrKs, Trk inhibitors
Abstract: Neurotrophins (NTs) and their receptors, TrKs and p75NTR, have been shown to regulate proliferation and apoptosis of neoplastic cells. Pharmacological TrK blockade is considered a valuable target in cancer therapy, and several TrK inhibitors are under investigation. However, only a few of them have reached the stage of clinical development. Myosarcomas are aggressive cancers, which secrete NGF and respond poorly to available chemotherapies. Our previous work has shown that these cancers, characterized by autocrine activation of TrKA by NGF, which promotes cancer growth and survival, are highly susceptible to TrK blockade, both in vitro and in vivo. The same pattern has also been described in prostatic carcinoma. The present report characterizes for the first time the anti-proliferative and pro-apoptotic effects of the oxindole TrK inhibitor GW441756, in a panel of human myosarcomas and prostatic adenocarcinoma cell lines. Furthermore, we provide novel evidence that, in myosarcomas, characterized by a high-TrK/low-p75NTR phenotype, GW441756 upregulates p75NTR receptor expression, leading to apoptosis via caspase-3 activation. Altogether, our data expand the knowledge of the anti-neoplastic and pro-apoptotic mechanisms of GW441756, and of TrK inhibitors in general, lending further support to the therapeutic potential of TrK blockade in clinical oncology.
Export Options
About this article
Cite this article as:
M. Stabile Anna, Montagnoli Claudia, Pistilli Alessandra, Grazia Rambotti Maria, Pula Grazia and Rende Mario, Antiproliferative and Proapoptotic Effects of the TrK-inhibitor GW441756 in Human Myosarcomas and Prostatic Carcinoma, Current Signal Transduction Therapy 2013; 8 (1) . https://dx.doi.org/10.2174/1574362411308010010
DOI https://dx.doi.org/10.2174/1574362411308010010 |
Print ISSN 1574-3624 |
Publisher Name Bentham Science Publisher |
Online ISSN 2212-389X |
- Author Guidelines
- Graphical Abstracts
- Fabricating and Stating False Information
- Research Misconduct
- Post Publication Discussions and Corrections
- Publishing Ethics and Rectitude
- Increase Visibility of Your Article
- Archiving Policies
- Peer Review Workflow
- Order Your Article Before Print
- Promote Your Article
- Manuscript Transfer Facility
- Editorial Policies
- Allegations from Whistleblowers
- Announcements
Related Articles
-
Vaccination and Antiviral Treatment of Neglected Diseases Caused by Flaviviral Infections
Current Medicinal Chemistry Voltage-Gated Sodium Channels in Neurological Disorders
CNS & Neurological Disorders - Drug Targets Importance of Wnt Signaling in the Tumor Stroma Microenvironment
Current Cancer Drug Targets Prediction and Targeting of Interaction Interfaces in G-protein Coupled Receptor Oligomers
Current Topics in Medicinal Chemistry Biological Activity and Physicochemical Properties of Dipeptidyl Nitrile Derivatives Against Pancreatic Ductal Adenocarcinoma Cells
Anti-Cancer Agents in Medicinal Chemistry Exploring Mechanisms of MicroRNA Downregulation in Cancer
MicroRNA Effect of Synthetic Cannabinoid HU210 on Memory Deficits and Neuropathology in Alzheimers Disease Mouse Model
Current Alzheimer Research Classes of Sigma2 (σ2) Receptor Ligands: Structure Affinity Relationship (SAfiR) Studies and Antiproliferative Activity
Current Pharmaceutical Design PP2A and Alzheimer Disease
Current Alzheimer Research CD248: Reviewing its Role in Health and Disease
Current Drug Targets Single-Photon Emission Computed Tomography Tracers for Predicting and Monitoring Cancer Therapy
Current Pharmaceutical Biotechnology A New Investigational Perspective for Purines Against Glioblastoma Invasiveness
Current Drug Targets The Therapeutic Potential of Sigma (σ) Receptors for the Treatment of Central Nervous System Diseases: Evaluation of the Evidence
Current Pharmaceutical Design Nanoparticles: Functionalization and Multifunctional Applications in Biomedical Sciences
Current Medicinal Chemistry Recent Advances and Approaches in Targeting Apoptosis Signaling Pathways for Anti-Cancer Therapeutics
Current Cancer Therapy Reviews The Current Chemical Utility of Marine and Terrestrial Filamentous Fungi in Side-Chain Chemistry
Current Organic Chemistry Spectroscopic Characterization of a Pyridine Alkaloid from an Endophytic Strain of the Fusarium incarnatum-equiseti Species Complex
Current Bioactive Compounds Inhibition of Protein Misfolding and Aggregation by Small Rationally-Designed Peptides
Current Pharmaceutical Design Nonsteroidal Anti-Inflammatory Drugs in Experimental Parkinsonian Models and Parkinsons Disease
Current Pharmaceutical Design Long Non-Coding RNA: An Emerging Paradigm of Pancreatic Cancer
Current Molecular Medicine