Abstract
Radiotherapy (RT) allows for tumor control through the cytotoxic action of ionizing radiation (IR). Although modern technologies permit precise IR delivery to the tumor mass while minimizing exposure of surrounding healthy tissues, the efficacy of RT remains limited by the intrinsic or acquired radioresistance of many tumors. There is thus an ongoing search for agents that augment the sensitivity of tumor cells to IR cytotoxicity, with recent interest in targeting components of signaling pathways involved in tumor growth and radioresistance. Here, we review the evidence suggesting that disabling one of these components, the mechanistic target of rapamycin (mTOR) kinase, may enhance RT efficacy. This molecule constitutes the catalytic subunit of the mTORC1 and mTORC2 protein complexes, which regulate cell growth and other processes implicated in tumorigenesis. Much work has focused on mTORC1 because it is selectively blocked by the microbial product rapamycin and its analogs (collectively designated rapamycins) that are approved for cancer treatment, and is frequently hyperactivated in malignant cells. In several, but not all human cancer cell lines, rapamycins increased IR cytotoxicity in vitro, apparently through multiple mechanisms, including the promotion of autophagic cell death. Rapamycins also potentiated fractionated RT in tumor xenograft models, in part by suppressing tumor angiogenesis. Synthetic kinase inhibitors that simultaneously target PI3K and both mTOR complexes also enhanced RT in vitro and in vivo, but with greater efficiency than rapamycins. These encouraging data have led to early clinical trials of rapamycins and catalytic mTOR inhibitors combined with RT in various cancers.
Keywords: Autophagy, cancer therapy, ionizing radiation, mTOR signaling, mTORC1, mTORC2, radiotherapy, radiosensitization, rapamycins
Current Cancer Drug Targets
Title:Disrupting the mTOR Signaling Network as a Potential Strategy for the Enhancement of Cancer Radiotherapy
Volume: 12 Issue: 8
Author(s): Francis J. Dumont and Pierre Bischoff
Affiliation:
Keywords: Autophagy, cancer therapy, ionizing radiation, mTOR signaling, mTORC1, mTORC2, radiotherapy, radiosensitization, rapamycins
Abstract: Radiotherapy (RT) allows for tumor control through the cytotoxic action of ionizing radiation (IR). Although modern technologies permit precise IR delivery to the tumor mass while minimizing exposure of surrounding healthy tissues, the efficacy of RT remains limited by the intrinsic or acquired radioresistance of many tumors. There is thus an ongoing search for agents that augment the sensitivity of tumor cells to IR cytotoxicity, with recent interest in targeting components of signaling pathways involved in tumor growth and radioresistance. Here, we review the evidence suggesting that disabling one of these components, the mechanistic target of rapamycin (mTOR) kinase, may enhance RT efficacy. This molecule constitutes the catalytic subunit of the mTORC1 and mTORC2 protein complexes, which regulate cell growth and other processes implicated in tumorigenesis. Much work has focused on mTORC1 because it is selectively blocked by the microbial product rapamycin and its analogs (collectively designated rapamycins) that are approved for cancer treatment, and is frequently hyperactivated in malignant cells. In several, but not all human cancer cell lines, rapamycins increased IR cytotoxicity in vitro, apparently through multiple mechanisms, including the promotion of autophagic cell death. Rapamycins also potentiated fractionated RT in tumor xenograft models, in part by suppressing tumor angiogenesis. Synthetic kinase inhibitors that simultaneously target PI3K and both mTOR complexes also enhanced RT in vitro and in vivo, but with greater efficiency than rapamycins. These encouraging data have led to early clinical trials of rapamycins and catalytic mTOR inhibitors combined with RT in various cancers.
Export Options
About this article
Cite this article as:
J. Dumont Francis and Bischoff Pierre, Disrupting the mTOR Signaling Network as a Potential Strategy for the Enhancement of Cancer Radiotherapy, Current Cancer Drug Targets 2012; 12 (8) . https://dx.doi.org/10.2174/156800912803251243
DOI https://dx.doi.org/10.2174/156800912803251243 |
Print ISSN 1568-0096 |
Publisher Name Bentham Science Publisher |
Online ISSN 1873-5576 |
Call for Papers in Thematic Issues
Advances in Cancer Biomarkers and Potential Drug Targets: From Diagnosis to Therapy
Cancer biomarkers play a crucial role in the diagnosis, prognosis, and treatment of cancer. They provide valuable information for cancer detection, risk assessment, treatment selection, and monitoring response to therapy. With advancements in molecular biology and high-throughput technologies, there has been an increasing interest in identifying and characterizing cancer biomarkers ...read more
Novel Therapeutic Approaches to Target Drug Resistant Tumors
With the development of disciplines such as chemical biology and molecular biology, the genes or proteins closely related to tumor occurrence and development have gradually become clear. Targeted therapies targeting these genes or proteins provide more effective methods for tumor treatment. Tumor targeted drugs generally only act on specific targets ...read more
ROLE OF IMMUNE AND GENOTOXIC RESPONSE BIOMARKERS IN TUMOR MICROENVIRONMENT IN CANCER DIAGNOSIS AND TREATMENT
Biological biomarkers have been used in medical research as an indicator of a normal or abnormal process inside the body, or of a disease. Nowadays, various researchers are in process to explore and investigate the biological markers for the early assessment of cancer. DNA Damage response (DDR) pathways and immune ...read more
Targeting the battlefield between host and tumor: basic research and clinical practice on reshaping tumor immune microenvironment
Immune system protects host against malignant tumors through effector cells and molecules. Cancer development and its response to therapy are regulated by inflammation, which either promotes or suppresses cancer progression. Chronic inflammation facilitates cancer progression and treatment resistance, whereas induction of acute inflammatory reactions often lead to anti-cancer immune responses. ...read more
- 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
Related Articles
-
SERMs: Evolutionary Chemistry, Revolutionary Biology
Current Pharmaceutical Design Antiproliferative Effects of Ocimum basilicum Methanolic Extract and Fractions, Oleanolic Acid and 3-epi-Ursolic Acid
Current Traditional Medicine Editorial [Hot topic: Receptor-Targeted Cancer Therapy (Guest Editor: Li-Chun Sun)]
Current Drug Delivery Insights Into the Molecular Aspects of Neuroprotective Bacoside A and Bacopaside I
Current Neuropharmacology Bitter Gourd (Momordica charantia) is a Cornucopia of Health: A Review of its Credited Antidiabetic, Anti-HIV, and Antitumor Properties
Current Molecular Medicine Nanostructure Thin Films of Titanium Dioxide Coated on Glass and Its Anti UV Effect for Living Organisms
Current Nanoscience Overview of Computer Aided Detection and Computer Aided Diagnosis Systems for Lung Nodule Detection in Computed Tomography
Current Medical Imaging Cytotoxicity Evaluation of Dimethoxy and Trimethoxy Indanonic Spiroisoxazolines Against Cancerous Liver Cells
Current Chemical Biology Deep Sequencing Approaches to Antibody Discovery
Current Drug Discovery Technologies Protecting Skin Photoaging by NF-κB Inhibitor
Current Drug Metabolism The Role of Inflammatory Response in Stroke Associated Programmed Cell Death
Current Neuropharmacology Cilengitide: The First Anti-Angiogenic Small Molecule Drug Candidate. Design, Synthesis and Clinical Evaluation
Anti-Cancer Agents in Medicinal Chemistry Strategy of Computer-Aided Drug Design
Current Drug Targets - Infectious Disorders Combating Hepatitis C Virus by Targeting MicroRNA-122 Using Locked Nucleic Acids
Current Gene Therapy Arsenic-exposed Keratinocytes Exhibit Differential microRNAs Expression Profile; Potential Implication of miR-21, miR-200a and miR-141 in Melanoma Pathway
Clinical Cancer Drugs Fluorescein-Inspired Near-Infrared Chemodosimeter for Luminescence Bioimaging
Current Medicinal Chemistry Efficacy of High-Dose Vitamin D Supplementation in the Critically Ill Patients
Inflammation & Allergy - Drug Targets (Discontinued) Acute Hypersensitivity Reactions to Chemotherapy Agents: An Overview
Inflammation & Allergy - Drug Targets (Discontinued) Therapeutic Approaches for the Treatment of Epidermal Growth Factor Receptor Mutated Lung Cancer
Current Cancer Drug Targets Exosomal microRNAs as Potentially Useful Tools in Cancer Biomarker Discovery
Recent Patents on Biomarkers