Abstract
The PI3K/Akt signaling pathway mediates mitogen-dependent growth and survival in various types of cancer cells, and inhibition of this pathway results in tumor cell growth arrest and apoptosis. Tocotrienols are natural forms of vitamin E that displays potent anticancer activity at treatment doses that had little or no effect on normal cell viability. Mechanistic studies revealed that the anticancer effects of γ-tocotrienol were associated with a suppression in PI3K/Akt signaling. Additional studies showed that cytotoxic LD50 doses of γ-tocotrienol were 3-5-fold higher than growth inhibitory IC50 treatment doses, suggesting that cytotoxic and antiproliferative effects of γ-tocotrienol might be mediated through different mechanisms. However, γ-tocotrienol-induced caspase activation and apoptosis in mammary tumor cells was also found to be associated with suppression in intracellular PI3K/Akt signaling and subsequent down-regulation of FLIP, an endogenous inhibitor of caspase processing and activation. Since breast cancer cells are significantly more sensitive to the inhibitory effects of γ-tocotrienol on PI3K/Akt signaling than normal cells, these findings suggest that γ-tocotrienol may provide significant health benefits in reducing the risk of breast cancer in women. Studies have also shown that combined treatment of γ-tocotrienol with other chemotherapeutic agents can result in a synergistic anticancer response. Combination therapy was most effective when the anticancer mechanism of action of γ-tocotrienol is complimentary to that of the other drug and can provide significant health benefits in the prevention and/or treatment of breast cancer, while at the same time avoiding tumor resistance or toxic effects that is commonly associated with high dose monotherapy.
Keywords: Vitamin E, tocotrienols, PI3K, Akt, breast cancer.
Anti-Cancer Agents in Medicinal Chemistry
Title:Tocotrienols Target PI3K/Akt Signaling in Anti-Breast Cancer Therapy
Volume: 13 Issue: 7
Author(s): Paul W. Sylvester and Nehad M. Ayoub
Affiliation:
Keywords: Vitamin E, tocotrienols, PI3K, Akt, breast cancer.
Abstract: The PI3K/Akt signaling pathway mediates mitogen-dependent growth and survival in various types of cancer cells, and inhibition of this pathway results in tumor cell growth arrest and apoptosis. Tocotrienols are natural forms of vitamin E that displays potent anticancer activity at treatment doses that had little or no effect on normal cell viability. Mechanistic studies revealed that the anticancer effects of γ-tocotrienol were associated with a suppression in PI3K/Akt signaling. Additional studies showed that cytotoxic LD50 doses of γ-tocotrienol were 3-5-fold higher than growth inhibitory IC50 treatment doses, suggesting that cytotoxic and antiproliferative effects of γ-tocotrienol might be mediated through different mechanisms. However, γ-tocotrienol-induced caspase activation and apoptosis in mammary tumor cells was also found to be associated with suppression in intracellular PI3K/Akt signaling and subsequent down-regulation of FLIP, an endogenous inhibitor of caspase processing and activation. Since breast cancer cells are significantly more sensitive to the inhibitory effects of γ-tocotrienol on PI3K/Akt signaling than normal cells, these findings suggest that γ-tocotrienol may provide significant health benefits in reducing the risk of breast cancer in women. Studies have also shown that combined treatment of γ-tocotrienol with other chemotherapeutic agents can result in a synergistic anticancer response. Combination therapy was most effective when the anticancer mechanism of action of γ-tocotrienol is complimentary to that of the other drug and can provide significant health benefits in the prevention and/or treatment of breast cancer, while at the same time avoiding tumor resistance or toxic effects that is commonly associated with high dose monotherapy.
Export Options
About this article
Cite this article as:
Sylvester W. Paul and Ayoub M. Nehad, Tocotrienols Target PI3K/Akt Signaling in Anti-Breast Cancer Therapy, Anti-Cancer Agents in Medicinal Chemistry 2013; 13 (7) . https://dx.doi.org/10.2174/18715206113139990116
DOI https://dx.doi.org/10.2174/18715206113139990116 |
Print ISSN 1871-5206 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-5992 |
Call for Papers in Thematic Issues
Induction of cell death in cancer cells by modulating telomerase activity using small molecule drugs
Telomeres are distinctive but short stretches present at the corners of chromosomes and aid in stabilizing chromosomal makeup. Resynthesis of telomeres supported by the activity of reverse transcriptase ribonucleoprotein complex telomerase. There is no any telomerase activity in human somatic cells, but the stem cells and germ cells undergone telomerase ...read more
Role of natural compounds as anti anti-cancer agents
Cancer is considered the leading cause of worldwide mortality, accounting for nearly 10 million deaths in 2022. Cancer outcome can be improved through an appropriate screening and early detection and through an efficient clinical treatment. Chemotherapy remains an important approach in treatment o f several types of cancers, even though ...read more
Signaling and enzymatic modulators in cancer treatment
Cancer accounts for nearly 10 million deaths in 2022 and is considered the leading cause of worldwide mortality. Cancer outcome can be improved through an appropriate screening and early detection and through an efficient clinical treatment. Chemotherapy, radiotherapy and surgery are the most important approach for the treatment of several ...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
-
Cholinergic Targets in Lung Cancer
Current Pharmaceutical Design Potential of Modulating Wnt Signaling Pathway Toward the Development of Bone Anabolic Agent
Current Molecular Pharmacology Functionalized magnetic nanoparticles for biomedical applications
Current Pharmaceutical Design Membrane-Targeted Self-Assembling Cyclic Peptide Nanotubes
Current Topics in Medicinal Chemistry Diverse Thiophenes as Scaffolds in Anti-cancer Drug Development: A Concise Review
Mini-Reviews in Medicinal Chemistry Beyond Hemostasis: The Role of Platelets in Inflammation, Malignancy and Infection
Cardiovascular & Hematological Disorders-Drug Targets Targeting Key Transporters in Tumor Glycolysis as a Novel Anticancer Strategy
Current Topics in Medicinal Chemistry Sympathetic Signaling in Angiogenesis: Implications for Cancer Progression
Current Cancer Therapy Reviews Nutraceuticals for Protection and Healing of Gastrointestinal Mucosa
Current Medicinal Chemistry Classical Inhibitors of NOX NAD(P)H Oxidases Are Not Specific
Current Drug Metabolism The Impact of Proteomics in the Understanding of the Molecular Basis of Paclitaxel-Resistance in Ovarian Tumors
Current Cancer Drug Targets A Transporter Gene (Sodium Iodide Symporter) for Dual Purposes in Gene Therapy: Imaging and Therapy
Current Gene Therapy Some Personal Memories of Bob Chanock
Infectious Disorders - Drug Targets Group-sparse Modeling Drug-kinase Networks for Predicting Combinatorial Drug Sensitivity in Cancer Cells
Current Bioinformatics Overcoming the Drug Resistance Problem with Second-Generation Tyrosine Kinase Inhibitors: From Enzymology to Structural Models
Current Medicinal Chemistry Histone Modifications, Stem Cells and Prostate Cancer
Current Pharmaceutical Design Biosafety of Recombinant Adeno-associated Virus Vectors
Current Gene Therapy Eco-Friendly and Highly Efficient Multigram Synthesis of N-(2- Hydroxyethyl)-2-Oxo-2H-Chromene-3-Carboxamide as a Useful Intermediate Using Sonochemistry
Current Green Chemistry How to Inhibit Telomerase Activity for Cancer Therapy
Current Medicinal Chemistry - Anti-Cancer Agents Natural Aristolochia Alkaloid Aristololactam-β-D-glucoside: Interaction with Biomacromolecules and Correlation to the Biological Perspectives
Mini-Reviews in Medicinal Chemistry