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Elsherbiny M.E.,University of Alberta | Emara M.,University of Alberta | Emara M.,Center for Aging and Associated Diseases | Godbout R.,University of Alberta
Progress in Lipid Research | Year: 2013

Malignant gliomas are the most common adult brain cancers. In spite of aggressive treatment, recurrence occurs in the great majority of patients and is invariably fatal. Polyunsaturated fatty acids are abundant in brain, particularly ω-6 arachidonic acid (AA) and ω-3 docosahexaenoic acid (DHA). Although the levels of ω-6 and ω-3 polyunsaturated fatty acids are tightly regulated in brain, the ω-6:ω-3 ratio is dramatically increased in malignant glioma, suggesting deregulation of fundamental lipid homeostasis in brain tumor tissue. The migratory properties of malignant glioma cells can be modified by altering the ratio of AA:DHA in growth medium, with increased migration observed in AA-rich medium. This fatty acid-dependent effect on cell migration is dependent on expression of the brain fatty acid binding protein (FABP7) previously shown to bind DHA and AA. Increased levels of enzymes involved in eicosanoid production in FABP7-positive malignant glioma cells suggest that FABP7 is an important modulator of AA metabolism. We provide evidence that increased production of eicosanoids in FABP7-positive malignant glioma growing in an AA-rich environment contributes to tumor infiltration in the brain. We discuss pathways and molecules that may underlie FABP7/AA-mediated promotion of cell migration and FABP7/DHA-mediated inhibition of cell migration in malignant glioma. © 2013 Elsevier Ltd. All rights reserved. Source


Emara M.,University of Alberta | Emara M.,Center for Aging and Associated Diseases | Turner A.R.,University of Alberta | Allalunis-Turner J.,University of Alberta
International Journal of Oncology | Year: 2014

Hemoglobin is produced mainly in erythroid cells. However, it has been reported in non-erythroid cells of human and rodents. We have shown previously that neuroglobin, cytoglobin and hemoglobin are expressed in human glioblastoma multiforme (GBM) cells. We sought to determine whether hemoglobin expression is upregulated by hypoxia, and whether its expression is restricted to the cancer stem cell populations in different GBM cell lines or GBM brain tumor initiating cells (BTICs). Flow cytometry, magnetic cell sorting and qRT-PCR were used to examine the hypoxic upregulation of hemoglobins as well as erythropoietin (EPO) and erythropoietin receptor (EPOR) in GBM cell lines (M006x, M059J, M059K, U87R and U87T) and GBM-BTICs. The data showed significantly increased expression in globins (α, β, γ, δ, ζ and ε), EPO and EPOR mRNA levels under hypoxia. Globin expression is not limited to the stem cell populations or GBM-BTICs but is a property of the entire GBM population. We assumed that the total expression of mRNA of different normalized globins (α, β, γ, δ, ζ and ε) at different time-points for the same cell line is 100%. Under aerobic conditions, ε globin was predominantly expressed, and then decreased gradually with increasing time in hypoxia. This was coupled to a concomitant increase in α and γ globins. Our findings suggest that hypoxic upregulation of hemoglobin expression in GBM cells may be a part of a repertoire of active defence and adaptation mechanisms enabling these cells to acquire resistance to aggressive multimodality treatments of chemotherapy and radiotherapy. New therapeutic strategies to interfere with hemoglobin expression or function in GBM cells are required. Source


Belousova V.,Albany College of Pharmacy and Health Sciences | Abd-Rabou A.A.,Albany College of Pharmacy and Health Sciences | Abd-Rabou A.A.,National Research Center of Egypt | Abd-Rabou A.A.,Center for Aging and Associated Diseases | Mousa S.A.,Albany College of Pharmacy and Health Sciences
Pharmacology and Therapeutics | Year: 2015

Current estimates indicate that the hepatitis C virus is the leading cause of death in the United States with infection rates steadily increasing. Successful treatment is made difficult by the presence of various host, virus, and treatment-related factors, warranting the development of new approaches to combat the silent epidemic. The addition of telaprevir and boceprevir to the pharmacotherapeutic arsenal drastically improved success rates in genotype 1 infected patients, but rapid development of resistance mechanisms, increases in adverse effects, and a low spectrum activity proved to be barriers to efficacious treatment. In late 2013, two new agents were approved - sofosbuvir and simeprevir - that have higher barriers to resistance, favorable safety profiles, and profoundly improved success rates; however higher costs associated with the new medications could limit their wider utilization. Further strategies to combat the virus are under development, ranging from interferon-free regimens as well as prophylactic and therapeutic vaccines to applications of nanotechnology, helping us get closer to improved treatment of patients infected with hepatitis C. © 2014 Elsevier Inc. Source


Abd-Rabou A.A.,National Research Center of Egypt | Abd-Rabou A.A.,Center for Aging and Associated Diseases
Indian Journal of Clinical Biochemistry | Year: 2016

The story of the cell commonder, calcium, reaches into all corners of the cell and controls cell proliferation, differentiation, function, and even death. The calcium-driven eukaryotic revolution is one of the great turning points in the life history, happened about two billion years later when it was converted from a dangerous killer that had to be kept out of cell into the cell master which drives the cell. This review article will take the readers to a tour of tissues chosen to best show the calcium’s many faces (proliferator, differentiator, and killer). The reader will first see calcium and its many helpers, such as the calcium-binding signaler protein calmodulin, directing the key events of the cell cycle. Then the tour will move onto the colon to show calcium driving the proliferation of progenitor cells, then the differentiation and ultimately the programmed death of their progeny. Moreover, the reader will learn of the striking disabling and bypassing of calcium-dependent control mechanisms during carcinogenesis. Finally, recommendations should be taken from the underlying mechanisms through which calcium masters the presistance, progression, and even apoptosis of colorectal cancer cells. Thus, this could be of great interest for designing of chemoprevention protocols. © 2016 Association of Clinical Biochemists of India Source


Refaat A.,University of Toyama | Refaat A.,Center for Aging and Associated Diseases | Aminullah,University of Toyama | Zhou Y.,University of Toyama | And 8 more authors.
Biochemical and Biophysical Research Communications | Year: 2015

Abstract Epidermal growth factor receptor (EGFR) mutation is one of the hallmarks of cancer progression and resistance to anticancer therapies, particularly non-small cell lung carcinomas (NSCLCs). In contrast to the canonical EGFR activation in which tyrosine residues are engaged, we have demonstrated that the non-canonical pathway is triggered by phosphorylation of serine and threonine residues through p38 and ERK MAPKs, respectively. The purpose of this study is to investigate the role of non-canonical EGFR pathway in resistance mechanism against cisplatin treatment. Wild type and mutated (exon 19 deletion) EGFR-expressing cells responded similarly to cisplatin by showing MAPK-mediated EGFR phosphorylation. It is interesting that internalization mechanism of EGFR was switched from tyrosine kinase-dependent to p38-dependent fashions, which is involved in a survival pathway that counteracts cisplatin treatment. We therefore introduce a potential combinatorial therapy composed of p38 inhibition and cisplatin to block the activation of EGFR, therefore inducing cancer cell death and apoptosis. © 2015 Elsevier Inc. All rights reserved. Source

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