ABSTRACT
The increasing rate of autoimmune disorders and cancer in recent years has been a controversial issue in all aspects of prevention, diagnosis, prognosis and treatment. Among dietary factors, flavonoids have specific immunomodulatory effects that might be of importance to several cancers. Over different types of immune cells, T lymphocytes play a critical role in protecting the immune system as well as in the pathogenesis of specific autoimmune diseases. One of the important mediators of metabolism and immune system is mTOR, especially in T lymphocytes. In the current review, we assessed the effects of flavonoids on the immune system and then their impact on the mTOR pathway. Flavonoids can suppress mTOR activity and are consequently able to induce the T regulatory subset.
Subject(s)
Flavonoids/pharmacology , Immunologic Factors/pharmacology , Immunomodulation/drug effects , Animals , CD4-Positive T-Lymphocytes/drug effects , CD4-Positive T-Lymphocytes/immunology , CD4-Positive T-Lymphocytes/metabolism , Energy Metabolism/drug effects , Humans , Immune System Phenomena/drug effects , Phosphatidylinositol 3-Kinases/metabolism , Proto-Oncogene Proteins c-akt/metabolism , Signal Transduction/drug effects , T-Lymphocytes, Regulatory/drug effects , T-Lymphocytes, Regulatory/immunology , T-Lymphocytes, Regulatory/metabolism , TOR Serine-Threonine Kinases/metabolismABSTRACT
OBJECTIVES: Monoclonal antibody-based of cancer therapy has been considered as one of the most successful therapeutic strategies for both haematologic malignancies and solid tumours in the last two decades. Epidermal growth factor receptor (EGFR) family signalling pathways play a key role in the regulation of cell proliferation, survival and differentiation. Hence, anti-EGFR family mAbs is one of the most promising approaches in cancer therapy. KEY FINDINGS: Here, recent advances in anti-EGFR mAb including approved or successfully tested in preclinical and clinical studies have been reviewed. Although we focus on monoclonal antibodies against the EGF receptor, but the mechanisms underlying the effects of EGFR-specific mAb in cancer therapy, to some extend the resistance to existing anti-EGFR therapies and some therapeutic strategies to overcome resistance such as combination of mAbs on different pathways are briefly discussed as well. SUMMARY: The EGFR family receptors, is considered as an attractive target for mAb development to inhibit their consecutive activities in tumour growth and resistance. However, due to resistance mechanisms, the combination therapies may become a good candidate for targeting EGFR family receptors.
Subject(s)
Antibodies, Monoclonal/therapeutic use , Antineoplastic Agents, Immunological/therapeutic use , ErbB Receptors/antagonists & inhibitors , Molecular Targeted Therapy/methods , Animals , HumansABSTRACT
According to the World Health Organization (WHO) published data in 2015; breast cancer is the most prevalent and the second leading cause of cancer death among females. As approximately 70% of breast cancer tumor cells are estrogen receptor (ER) positive, primary therapeutic agents such as Anti-estrogens were produced mostly in a way to target this receptor. Anti-estrogen therapies mostly target Estrogen receptor and block its underlying signaling pathways. Nevertheless, resistance to these agents made the condition more complicated. Recently the role of one molecule in the resistance development has been studied in some cases: ER-α36 is a 36 kDa variant of estrogen receptor molecule which is mostly absent in normal breast cells. Its interactions with epidermal growth factor receptors and ER-α66 leads in over-activation and/or over-expression of estrogen-independent pathways and suppression of estrogen-dependent pathways; they all in turn, will maintain tumor cell's growth even in the presence of tamoxifen. In this mini-review, we mainly surveyed different pathways which ER-α36 could lead to tamoxifen resistance. We also briefly mentioned how ER-α36 could switch the growth cascades from estrogen dependent into independent and make this resistance network become even more complicated.
Subject(s)
Breast Neoplasms/metabolism , Drug Resistance, Neoplasm/physiology , Estrogen Receptor alpha/metabolism , Tamoxifen/therapeutic use , Breast Neoplasms/drug therapy , Breast Neoplasms/pathology , Cell Proliferation/drug effects , Cell Proliferation/physiology , Female , Humans , Signal Transduction/drug effects , Signal Transduction/physiologyABSTRACT
Breast cancer-related deaths have been on the decline ever since the application of systemic therapies. Chiefly, endocrine therapy, such as Tamoxifen, enhances the survival of estrogen receptor (ER)-positive patients. More than a decade has passed since the introduction of Tamoxifen, however, drug resistance, particularly to Tamoxifen, still remains a major challenge. It has been shown that not only does chronic Tamoxifen exposures induce resistance, but estrogen deprivation can as well. There are two Tamoxifen resistant cell lines, long term estrogen deprived (LTED) cells and cells that have acquired resistance due to long-term exposure to Tamoxifen (Tam-R). Despite having similar cytosolic pathways over-activated in Tam-R and LTED-R cells during the development of resistance, the administration of receptor tyrosine kinases (RTKs) inhibitors fail to restore Tamoxifen sensitivity in LTED-Rs. This alludes to existing differences in the underlying molecular mechanisms of resistance. Surprisingly, despite estrogen being recognized as a breast cancer stimulator; it has recently been introduced as an apoptotic inducer in unresponsive cells. Furthermore, the addition of estrogen to the media of LTED and Tam-R cells triggers cell death, perhaps is functioning as an anti-proliferative agent. In this review, we outline the molecular pathways potentially facilitating estrogen-induced apoptosis in resistant cells.