Current Pharmaceutical Biotechnology - Volume 15, Issue 12, 2014

Pathogenesis of tuberculosis is marked with infection of macrophages followed by expansion of M. tuberculosis. Every step of this host-pathogen interaction is determined by the battle between the pathogen and host immune factors. It starts with phagocytosis of bacilli by mononuclear cells including alveolar macrophages and Dendritic Cells (DCs), both of which are Antigen Presenting Cells (APCs). Phagocytosed M. tuberculosis is subject to degradation by various means inside the phagolysosome. This very specific anti-M. tuberculosis mechanism within the phagocytes is well orchestrated. Upon activation, macrophages exhibit elevated levels of various intermediates via the oxidative burst, which effectively kills the pathogen and inhibits its dissemination. Generation of these intermediates and then their neutralization is intricately linked with the balance of divalent and trivalent iron metals in and outside of the cell. This review will bring the insight of host-M. tuberculosis interaction and its effectiveness in containment of the disease. Furthermore, the physiological balance of iron, its pathogen driven perturbance as well as its effect on the disease will also be discussed.

Cancer is the manifestation of multiple dysregulated cellular pathways. Treatment protocols engaged in treating these diseases involve mainly the cell cycle regulating genes/proteins, DNA synthesis and repair, protein synthetic machinery, apoptotic and proliferation activity and cytoskeletal framework. Some of the traditional therapeutic strategies have over the years developed resistance making cure difficult to achieve. This paper analyzes the mechanisms employed by various cancers that render them resistant against therapeutic drugs.

Breast cancer is a prominent cause of mortality in women worldwide, with about 2/3rd cases linked to hormone mediated malignancy itself. A hormone receptor positive breast cancer represents cells showing rigorous proliferation upon hormonal exposure. BRCA1 is the predominant marker gene responsible for estrogen regulation. However increased exposure to estrogen is not the sole cause for this abnormality as there is no significant alteration reported in breast tissue estrogen levels. Iron metabolism has also been shown to be frequently altered in breast cancer with considerably higher iron in post menstrual women. In fact estrogen and iron have been implicated to exert synergistic effects on cellular proliferation in BRCA1 linked hormone responsive breast cancer. Thus establishing a link between estrogen and iron metabolism has a great prognostic value in predicting clinical outcome in BRCA1 linked hormone responsive breast cancer patients. Since the time immemorial Iron chelators have been implicated in combating iron dysregulation especially in breast cancer. We summarize here in this review the recent advancements in the area of iron chelation therapy delineating the role of iron in hormone receptor positive Breast cancer.

Iron metabolism and homeostasis are imperative for the maintenance of normal physiological activities due to the element’s critical involvement in a wide variety of crucial biological processes like cellular respiration, metabolic pathways, DNA replication, repair, detoxification, neurotransmission and cellular signaling. Being a key contributor of crucial machineries regulating cellular proliferation and survival, it facilitates the process of tumor growth and development. Thus, tumor cells strive to acquire higher amount of iron than non-malignant cells to satisfy their elevated rate of metabolism. Perhaps, not surprisingly chelation of this metal ion was thought to be effective in treating cancer, but due to a variety of side effects, the use of iron chelators was clinically insignificant. However, discovery of various new classes of iron chelators with lesser side effects and selective toxicity towards cancer cells has revived the possibilities of using iron chelators in anti-cancer therapy. In this review, we have discussed the role of iron in promoting malignant mechanisms and the prospects of usage of different classes of iron chelators in cancer therapeutics.

Estrogens along with their receptors are required for the normal physiological development of women. However, in altered physiological conditions a high level of estrogens acts either as initiator or progressor of breast cancer. Approximately in 75% of estrogen dependent breast cancer cases estrogen receptors (ERs) are held responsible. Recent studies indicate that estrogens along with iron (Fe) concomitantly involved in the proliferation of ER+ breast cancer cells. While a number of antiestrogen/anti-ER drugs including selective estrogen receptor modulators (SERMs), aromatase inhibitors (AIs) and selective estrogen receptor down regulators (SERDs) are used to eradicate breast cancer but their action on Fe dependent breast cancer complication is not yet explored. Moreover, many of the ER+ breast cancer patients receiving anti-estrogen drugs relapsed within a couple of years and become resistant to antiestrogen therapy. Mutation and loss of affinity to the target molecule (ERs), loss or overexpression of ERs, along with activation of growth promoting pathways alternative to estrogen-ER pathways are the major reasons of drug resistance. Combinational therapy may be best alternative to antiestrogen relapsed patients. Some of the widely studied drug combinations are roscovitine (ROSC) and tamoxifen, metformin and tamoxifen, tamoxifen and RAD001. While in all these drug combinations anti-ER compound tamoxifen may be one of the major content, anti-Fe compounds are yet to be used as drug combination. The present review article describes all the currently studied drugs/drug combinations in ER+ breast cancer cells and future drug possibilities including anti-Fe compounds.

Tuberculosis is one of the leading global health issues responsible for a significant mortality. The emergence of multidrug resistant (MDR), extensively drug resistant (XDR) and total drug resistant (TDR) strains have further hampered the disease control. Drug resistance has emerged as imperative concern resulting in genetic selection of drug resistance strains making them unresponsive to most of the drugs. In addition iron has been implicated in promoting Mycobacterium tuberculosis (MTB) replication, infection and progression to clinical disease. ideR is an essential gene in Mycobacterium tuberculosis and controls the transcription of mycobacterium by binding to promoters of ideR regulated gene in presence of iron. Iron chelators have the potential to sequester this excess iron hence hampering MTB replication and restoring host defence mechanisms. Iron chelators could be envisaged as promising candidates in iron overload associated prevention and treatment of MTB.

The scenario of tuberculosis has gone deadly due to its high prevalence and emergence of widespread drug resistance. It is now high time to develop novel antimycobacterial strategies and to understand novel mechanisms of existing antimycobacterial compounds so that we are equipped with newer tuberculosis controlling molecules in the days to come. Iron has proven to be essential for pathogenesis of tuberculosis and retinoic acid is known to influence the iron metabolism pathway. Retenoic acid is also known to exhibit antitubercular effect in in vivo system. Therefore there is every possibility that retinoic acid by affecting the iron metabolism pathway exhibits its antimycobacterial effect. These aspects are reviewed in the present manuscript for understanding the antimycobacterial role of retinoic acid in the context of iron metabolism and other immunological aspects.

In the development of atherosclerosis, naringin has exhibited potential protective effects. However, the specific mechanisms are not clearly understood. The aim of this trial was to determine the anti-oxidative and anti-inflammatory effects of naringin and uncover the mechanisms in Tumor Necrosis Factor-alpha (TNF-α) induced Human Umbilical Vein Endothelial Cells (HUVECs). Reactive Oxygen Species (ROS) were measured by flow cytometry assay. The levels of NADPH oxidase 4 (Nox4), p22phox, intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) over-expressions were measured by qRT-PCR and Western blotting analyses. Activation of Phosphatidylinositol 3-kinase/Akt (PI3K/Akt) and Nuclear Factor-ΚB (NF-ΚB) was evaluated by Western blotting. Naringin inhibited ROS production as well as over-expression levels of Nox4, p22phox induced by TNF-α. Naringin inhibited TNF-α induced mRNA and protein over-expressions of ICAM-1 and VCAM-1. Naringin also suppressed activation of NF-ΚB and PI3K/Akt signaling pathways. These results indicated the preventive effects of naringin on HUVECs injury caused by oxidative stress and inflammation response and the effects might be obtained via inhibition of Nox4 and NF-ΚB pathways as well as activation of PI3K/Akt pathway. Naringin may be useful in preventing endothelial dysfunction, therefore to ameliorate the development of atherosclerosis.