Most of the cancer related deaths are caused mainly by metastasis. Therefore, it is highly important to unfold the major mechanisms governing metastasis process in cancer. Throughout the metastatic cascade, cells need the ability to survive without attachment to neighboring cells and the original Extra Cellular Matrix (ECM). Recent reports showed that loss of ECM attachment shifts cancer cell metabolism towards glycolysis mostly through hypoxia. However, AMPK, a master metabolic regulator was also found to be upregulated under ECM detached conditions. Therefore, in this work we aimed to understand the consequences of targeting AMPK and other metabolic kinases by a broad kinase inhibitor namely Compound C in ECM detached cancer cells. Results showed that Compound C impacts glycolysis as evident by increased levels of pyruvate, but reduces its conversion to lactate thereby negatively regulating the Warburg effect. Simultaneously, Compound C induces block at multiple levels in TCA cycle as evident from accumulation of various TCA metabolites. Interestingly Compound C significantly reduces glutamine and reduced glutathione levels, suggesting loss of antioxidant potential of ECM detached cancer cells. Further, we found increased in metabolites associated with nucleotide synthesis, one carbon metabolism and PPP pathway during Compound C treatment of ECM detached cells. Finally, we also found induction in metabolites associated with DNA damage in ECM detached cancer cells during Compound C treatment, suggesting DNA damage regulatory role of metabolic kinases. Overall, our results showed that Compound C represses pyruvate to lactate conversion, reduces antioxidant potential and invokes DNA damage in ECM detached cancer cells. Our data provides a comprehensive metabolic map of ECM detached cancer cells that can be targeted with a broad kinase inhibitor, is Compound C. The data can be used for designing new combinational therapies to eradicate ECM detached cancer cells.
Leukemia is persistently a significant cause of illness and mortality worldwide. Urolithins, metabolites of ellagic acid and ellagitannins produced by gut microbiota, showed better bioactive compounds liable for the health benefits exerted by ellagic acid and ellagitannins containing pomegranate and walnuts. Here, we assessed the potential antileukemic activities of both urolithin A and urolithin B. Results showed that both urolithin A and B significantly inhibited the proliferation of leukemic cell lines Jurkat and K562, among which urolithin A showed the more prominent antiproliferative capability. Further, urolithin treatment alters leukemic cell metabolism, as evidenced by increased metabolic rate and notable changes in glutamine metabolism, one-carbon metabolism, and lipid metabolism. Next, we evidenced that both urolithins equally promoted apoptosis in leukemic cell lines. Based on these observations, we concluded that both urolithin A and B alter leukemic cell metabolome, resulting in a halt of proliferation, followed by apoptosis. The data can be used for designing new combinational therapies to eradicate leukemic cells.
The current study is based on Zn/ZnO nanoparticles photodynamic therapy (PDT) mediated effects on healthy liver cells and cancerous cells. The synthesis of Zn/ZnO nanoparticles was accomplished using chemical and hydrothermal methods. The characterization of the synthesized nanoparticles was carried out using manifold techniques (e.g., transmission electron microscopy (TEM), X-ray diffraction (XRD), and energy dispersive X-ray spectroscopy (EDS)). In order to study the biotoxicity of the grown nanoparticles, they were applied individually and in conjunction with the third generation photosensitiser Fotolon (Chlorine e6) in the in vivo model of the normal liver of the Wister rat, and in the in vitro cancerous liver (HepG2) model both in the dark and under a variety of laser exposures (630 nm, Ultraviolet (UV) light). The localization of ZnO nanoparticles was observed by applying fluorescence spectroscopy on a 1 cm2 selected area of normal liver, whereas the in vitro cytotoxicity and reactive oxygen species (ROS) detection were carried out by calculating the loss in the cell viability of the hepatocellular model by applying a neutral red assay (NRA). Furthermore, a statistical analysis is carried out and it is ensured that the p value is less than 0.05. Thus, the current study has highlighted the potential for applying Zn/ZnO nanoparticles in photodynamic therapy that would lead to wider medical applications to improve the efficiency of cancer treatment and its biological aspect study.
Reactive Oxygen Species (ROS) are generated during normal cellular metabolic activity, especially in the electron transport chain and in biological redox reactions. Cumene Hydroperoxide, (CHP) a potent source of ROS, is commonly used in the chemical manufacture of phenols, acetone and polymers and can result in inadvertent exposure to individuals working in this chemical industry. CHP is known to initiate lipid peroxidation and increase ROS levels in membranes, which can lead to oxidative stress and cell death. The aim of the study was to investigate the cytoprotective activity of two flavonoids, catechin and epicatechin against the oxidative stress induced by CHP. The method involved comparing the % cell viability between cells treated with CHP for 4h alone and cells pretreated with catechin or epicatechin for 24 or 48 hr prior to treatment with CHP. MTS cell proliferation assays (Abcam) was used to determine cell viability after exposure. Approximately 1×104 cells/100μL/well of MCF‐7 cells were seeded in a 96‐well plates. After 24 hours, the cells were treated with CHP (50–350 μM) for 2h, 4h or 24h to determine viability. Cells were also treated with catechin (100–500μM), epicatechin (100–500μM), DMSO or control for 24 or 48 hr. Additionally, cells were pretreated with catechin (100–500μM) or epicatechin (100–500μM) and then exposed to 100μM CHP for 4 hours. % cell viability was then determined by the MTS assay system. The results of individual treatments indicated that there was a concentration dependent cell toxicity of CHP at concentrations > 50μM CHP compared to control when cells were exposed for 4 hr to CHP (IC50 = 100 μM). All concentrations of catechin and epicatechin showed no significant loss of cell viability as compared to the control after both 24 and 48h hr exposure. In the pre‐treatment studies, 100μM of CHP showed 50% decrease in cell viability after 4h of treatment, however when the cells were pretreated for 24 hr with catechin (400–500 μM) or epicatechin (400–500 μM) there was protection of 10–20% from the cytotoxic effects of CHP. Concentrations lower than 400 μM of catechin and epicatechin did not show protection. At 48h of pretreatment with catechin and epicatechin, enhanced protection (20 – 30 %), compared to the 24 hr pre‐treatment, was observed with 300–500 μM concentrations of catechin and epicatechin. The results clearly demonstrate that catechin and epicatechin at concentrations of 300 – 500 μM are cytoprotective to MCF‐7 cells against oxidative stress induced by exposure to 100 μM CHP.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
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