Nuclear factor erythroid-2 related factor-2 (Nrf2) is an oxidative stress-response transcriptional activator that promotes carcinogenesis through metabolic reprogramming, tumor promoting inflammation, and therapeutic resistance. However, the extension of Nrf2 expression and its involvement in regulation of breast cancer (BC) responses to chemotherapy remain largely unclear. This study determined the expression of Nrf2 in BC tissues (n = 46) and cell lines (MDA-MB-453, MCF-7, MDA-MB-231, MDA-MB-468) with diverse phenotypes. Immunohistochemical (IHC)analysis indicated lower Nrf2 expression in normal breast tissues, compared to BC samples, although the difference was not found to be significant. However, pharmacological inhibition and siRNA-induced downregulation of Nrf2 were marked by decreased activity of NADPH quinone oxidoreductase 1 (NQO1), a direct target of Nrf2. Silenced or inhibited Nrf2 signaling resulted in reduced BC proliferation and migration, cell cycle arrest, activation of apoptosis, and sensitization of BC cells to cisplatin in vitro. Ehrlich Ascites Carcinoma (EAC) cells demonstrated elevated levels of Nrf2 and were further tested in experimental mouse models in vivo. Intraperitoneal administration of pharmacological Nrf2 inhibitor brusatol slowed tumor cell growth . Brusatol increased lymphocyte trafficking towards engrafted tumor tissue in vivo, suggesting activation of anti-cancer effects in tumor microenvironment. Further large-scale BC testing is needed to confirm Nrf2 marker and therapeutic capacities for chemo sensitization in drug resistant and advanced tumors.

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Background: The demand for millet-based diets has increased significantly in recent years due to their beneficial effects on human health. Foxtail Millet (Setaria italica (L.) P.Beauv, previously known as Panicum italicum L., referred as FTM in this manuscript) seeds have been not only used as astringent and diuretic agents, but they are also used to treat dyspepsia and rheumatism. Recent studies have shown that solvent extracts from FTM seeds exhibited antioxidant and antiinflammatory activities. However, the nature and antiproliferative potential of phytochemical constituents of solvent extracts are not much explored. Objectives: Major objectives of this study are to generate and characterize the phytochemical-rich fractions from Foxtail millet seeds, test the antioxidant activity and antiproliferative potential against cell lines representing carcinomas of the breast, and determine the mechanism(s) of cell growth inhibition. Methods: Phytochemical-rich fractions were generated by extracting the seeds using 70% ethanol (FTM-FP) and 10% alkali (FTM-BP). Antioxidant potential was determined by ferric reducing antioxidant power (FRAP) assay and DPPH radical scavenging activity assays. The antiproliferative potential was determined using sulforhodamine-B assay. The impact on cell cycle and DNA fragmentation was analyzed by staining the cells with DAPI followed by analyzing the stained cells using NC-3000. Results: Analysis of the results showed the presence of phenolics and flavonoids in the FTM-FP and FTM-BP fractions. Both fractions exhibited antiproliferative potential against breast cancer cell lines. Mechanistically, both fractions induced G2/M cell cycle arrest and increased the fragmentation of DNA, which lead to the accumulation of cells in the Sub-G1 phase. Conclusion: In summary, results of this study demonstrated the potential of foxtail millet phytochemical fractions for retarding the proliferative potential of breast cancer cells.

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Shivagutika is a polyherbal formulation mentioned in Ayurveda, the oldest system of medicine. The aim of this study was to investigate the anti-breast cancer potential of DCM extract of Shivagutika using MCF-7, MDA-MB-231, and MDA-MB-468. Primarily, various extracts of Shivagutika were prepared and subjected to primary in vitro analysis—total protein, phenolic acid content, and flavonoid content. DCM extract among all the extracts showed the promising results hence, it was subjected to LC-MS/MS analysis to identify the phytochemicals. The same extract was subjected to anti-proliferation assay and anti-cancer assay. It inhibited all the 3 cell lines and increased the activity of Caspase 3, pro-apoptotic protein. Further, to find the potent molecule(s) in silico analysis (molecular docking and molecular dynamics simulation studies) was performed. Sciadopitysin was identified as a potent molecule among all phytochemicals as it interacted with Caspase 3 with a binding energy of −7.2 kcal/mol. MD simulation studies also revealed that Sciadopitysin was stable inside the binding pocket of Caspase 3 by interacting with the amino acids in the catalytic site thereby activating the Caspase 3 levels. By all the above results, Shivagutika could be used as a potent anti-breast cancer agent (specifically DCM extract of Shivagutika) which could decrease the cases of breast cancer in future.

Incidence of breast cancer in the age group of 30 to 50 is increasing at an alarming rate globally. Moreover, existing treatments are either marginally effective or resistance developed, hence development of safe and potent pharmacological agents is immediately required. However, establishment of a disease progression marker for early detection, development of safe and effective treatment agents requires identification of key proteins that are exclusively expressed in advanced malignant breast tumors. 2-Dimensional gel electrophoresis (2-DGE) is one of the early methods used for the identification of deregulated proteins in cancers. Therefore, the proteins of benign andmalignant tumors as well as breast cancer cell lines MCF-7, SKBR-3 and MDAMB- 468, were subjected to 2-DGE and relative expression calculated. Analysis of the data showed a significant increase in the intensity of 7 protein spots compared to malignant tissues and benign ones. Further, comparison of cell line proteins with tissue lysates revealed that SKBR-3 is much closer to malignant tumors, hence, may be considered for screening drug targets as well as for evaluating the efficacy of pharmacological agents. In conclusion, our 2-DGE identified key differences and similarities in the expression of proteins between breast cancer cell lines, benign and malignant tissues.

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