Breast cancer is one of the biggest global dilemmas and its current therapy is to target the hormone receptors by the use of partial agonists/antagonists. Potent drugs for breast cancer treatment are Tamoxifen, Trastuzumab, Paclitaxel, etc. which show adverse effects and resistance in patients. The aim of the study has been on certain phytochemicals which has potent actions on ERα, PR, EGFR and mTOR inhibition. The current study is performed by the use of molecular docking as protein-ligand interactions play a vital role in drug design. The 3D structures of ERα, PR, EGFR and mTOR were obtained from the protein data bank and docked with 23 3D PubChem structures of furanocoumarin compounds using FlexX. Drug-likeness property was checked by applying the Lipinski’s rule of five on the furanocoumarins to evaluate anti-breast cancer activity. Antagonist and inhibition assay of ERα, EGFR and mTOR respectively has been performed using appropriate in-vitro techniques. The results confirm that Xanthotoxol has the best docking score for breast cancer followed by Bergapten, Angelicin, Psoralen and Isoimperatorin. Further, the in-vitro results also validate the molecular docking analysis. This study suggests that the selected furanocoumarins can be further investigated and evaluated for breast cancer treatment and management strategies.

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T he endoplasmic reticulum (ER) is the port of entry into the secretory pathway. ER stress is a state of imbalance between the protein-folding capacities and the amount of proteins in the ER. A network of signaling pathways termed the unfolded protein response (UPR) restores the disrupted balance in the ER or executes apoptosis when ER stress becomes terminal. In mammalian cells, the UPR operates in three parallel pathways named for ER stress sensors: inositol-requiring enzyme 1 (IRE1), protein kinaselike endoplasmic reticulum kinase (PERK), and activating transcription factor 6 (ATF6). These sensors activate downstream signals that regulate gene transcription and protein synthesis (1).Following a signal to differentiate into plasma cells (PCs), the ER of a B cell expands and becomes permissive for the synthesis, proper folding, assembly, and secretion of copious amounts of antibodies. For reasons that are not fully understood, the remodeling of the ER in the course of PC differentiation is controlled solely by the IRE1/X-box binding protein 1 (XBP-1) pathway of the UPR (2, 3). In the absence of XBP-1 or IRE1, B cells develop normally to the mature state but yield long-lived PCs that secrete small amounts of Igs (4-7).Mammalian target of rapamycin (mTOR) is a key metabolic serine/threonine kinase which exists in at least two multisubunit complexes, referred to as mTOR complex 1 (mTORC1) and mTORC2 (8). mTORC1 funnels multiple signaling pathways from inside and outside the cell. When activated, mTORC1 promotes anabolic processes and enhances protein synthesis and cell growth (9). When it is inhibited, macroautophagy is induced (10). mTOR, primarily in the form of mTORC1, plays major roles in cancer and immune functions (11,12). Much of the knowledge on the role of mTOR in immune regulation has been obtained from loss-of-function experiments using rapamycin or analogs thereof. However, the effect that mTOR activation has on the immune system remains unclear. At the mature state of B cell development, mTOR is activated in response to Toll-like receptor and B cell receptor (BCR) stimulation downstream from the phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathway. Akt activates mTORC1 indirectly by reversing the tuber sclerosis complex (TSC) inhibition of mTOR. TSC is a complex that contains TSC1 and TSC2. Among many other functions, the mTOR pathway adjusts protein synthesis to the prosperity conditions of the cell. mTOR is activated when the ATP/AMP ratio or the intracellular pool of amino acids is high. The control of protein synthesis is regulated by mTOR-specific phosphorylation of 4E-BP1 and p70S6K1, both of which, when phosphorylated, mediate acceleration of protein synthesis and cell growth (13-15). Hence, inhibition of the mTOR globally reduces protein synthesis and cell size.We previously reported that mTOR is the predominant mechanism that controls protein synthesis in the late phase of lipopolysaccharide (LPS)-activated B cells, in a manner rigorously controlled by ER stress. Genetic ablation of TSC...

This review discusses plant-derived compounds with estrogenic activity. The authors rightly emphasize the need for the intake of foods containing phytoestrogens in view of their positive effects on postmenopausal indications. This is particularly significant in the light of the current wave of enthusiasm for vegetarian food, in general, and phytoestrogens, in particular. Phytoestrogens are plant-derived hormone-like diphenolic compounds of dietary origin. These compounds are weakly estrogenic and could play a role in the prevention of other estrogen-related conditions, namely, cardiovascular diseases, menopausal symptoms, postmenopausal osteoporosis, neuroprotective effects, and hormone-dependent cancers (breast and endometrium cancer).

Coumarins, identified as plant secondary metabolites possess diverse biological activities including anti-angiogenic properties. Daphnetin (DAP), a plant derived dihydroxylated derivative of coumarin has shown significant pharmacological properties such as anticancer, anti-arthritic and anti-inflammatory. The present study was performed to investigate the anti-angiogenic potential of DAP, focusing on the mechanism of action. The in vivo anti-angiogenic potential of DAP was evaluated by vascular endothelial growth factor (VEGF)-induced rat aortic ring (RAR) assay and chick chorioallantoic membrane (CAM) assay. For in vitro evaluation, wounding migration, transwell invasion, tube formation and apoptosis assays were performed on VEGF (8 ng/mL)-induced human umbilical vein endothelial cells (HUVECs). The cellular mechanism of DAP was examined on TNFα (10 ng/mL) and VEGF-induced HUVECs by extracting the mRNA and protein levels using RT-qPCR and western blotting. Our data demonstrated that DAP inhibited the in vivo angiogenesis in the RAR and CAM assay. DAP also inhibited the different steps of angiogenesis, such as migration, invasion, and tube formation in HUVECs. DAP inhibited nuclear factor-κB signalling together including TNF-α induced IκBα degradation; phosphorylation of IκB kinase (IKKα/β) and translocation of the NF-κB-p65 protein. Furthermore, western blotting revealed that DAP significantly down-regulated the VEGF-induced signalling such as c-Src, FAK, ERK1/2 and the related phosphorylation of protein kinase B (Akt) and VEGFR2 expressions. DAP reduced the elevated mRNA expression of iNOS, MMP2 and also, induced apoptosis in VEGF-stimulated HUVECs by the caspase-3 dependent pathway. Taken together, this study reveals that DAP may have novel prospective as a new multi-targeted medication for the anti-angiogenesis and cancer therapy.