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Alfarouk K.O.,University of Khartoum | Verduzco D.,H. Lee Moffitt Cancer Center and Research Institute | Rauch C.,University of Nottingham | Muddathir A.K.,University of Khartoum | And 8 more authors.
Oncoscience | Year: 2014

Cancer cells acquire an unusual glycolytic behavior relative, to a large extent, to their intracellular alkaline pH (pHi). This effect is part of the metabolic alterations found in most, if not all, cancer cells to deal with unfavorable conditions, mainly hypoxia and low nutrient supply, in order to preserve its evolutionary trajectory with the production of lactate after ten steps of glycolysis. Thus, cancer cells reprogram their cellular metabolism in a way that gives them their evolutionary and thermodynamic advantage. Tumors exist within a highly heterogeneous microenvironment and cancer cells survive within any of the different habitats that lie within tumors thanks to the overexpression of different membrane-bound proton transporters. This creates a highly abnormal and selective proton reversal in cancer cells and tissues that is involved in local cancer growth and in the metastatic process. Because of this environmental heterogeneity, cancer cells within one part of the tumor may have a different genotype and phenotype than within another part. This phenomenon has frustrated the potential of single-target therapy of this type of reductionist therapeutic approach over the last decades. Here, we present a detailed biochemical framework on every step of tumor glycolysis and then propose a new paradigm and therapeutic strategy based upon the dynamics of the hydrogen ion in cancer cells and tissues in order to overcome the old paradigm of one enzyme-one target approach to cancer treatment. Finally, a new and integral explanation of the Warburg effect is advanced. Source


Alfarouk K.O.,University of Khartoum | Stock C.-M.,University of Munster | Taylor S.,University of Nottingham | Walsh M.,University of Nottingham | And 9 more authors.
Cancer Cell International | Year: 2015

Cancer chemotherapy resistance (MDR) is the innate and/or acquired ability of cancer cells to evade the effects of chemotherapeutics and is one of the most pressing major dilemmas in cancer therapy. Chemotherapy resistance can arise due to several host or tumor-related factors. However, most current research is focused on tumor-specific factors and specifically genes that handle expression of pumps that efflux accumulated drugs inside malignantly transformed types of cells. In this work, we suggest a wider and alternative perspective that sets the stage for a future platform in modifying drug resistance with respect to the treatment of cancer. © 2015 Alfarouk et al. Source


Alfarouk K.O.,University of Khartoum | Stock C.-M.,University of Munster | Taylor S.,University of Nottingham | Walsh M.,University of Nottingham | And 10 more authors.
Cancer Cell International | Year: 2015

Cancer chemotherapy resistance (MDR) is the innate and/or acquired ability of cancer cells to evade the effects of chemotherapeutics and is one of the most pressing major dilemmas in cancer therapy. Chemotherapy resistance can arise due to several host or tumor-related factors. However, most current research is focused on tumor-specific factors and specifically genes that handle expression of pumps that efflux accumulated drugs inside malignantly transformed types of cells. In this work, we suggest a wider and alternative perspective that sets the stage for a future platform in modifying drug resistance with respect to the treatment of cancer. © 2015 Alfarouk et al. Source


Milosavljevic N.,University of Nice Sophia Antipolis | Blanchard A.,University of Nottingham | Wahl M.L.,U. Baltimore | Harguindey S.,Institute of Clinical Biology and Metabolism | And 3 more authors.
Recent Patents on Anti-Cancer Drug Discovery | Year: 2011

"How do drugs cross the plasma membrane?" this may seem like a trivial question. This question is often overlooked to focus primarily on the different complex macro-molecular aspects involved in drug delivery or drug resistance. However, recent studies have highlighted the theme that to be fully understood, more knowledge of the underlying biology of the most complex biological processes involved in the delivery and resistance to drugs is needed. After all, why would a drug interact with a transporter then subsequently be excluded from P-glycoprotein (P-gp) expressing drug resistant cells? What are the determinants of this transition in behavior? Full consideration of the physical biology of drug delivery has allowed a better understanding of the reasons why specific membrane proteins are upregulated or overexpressed in drug resistant cells. This, in turn, allows us to identify new targets for drug chemicals. Better yet, it increases the significance of recents patents and underlines their importance in multi drug resistance. © 2011 Bentham Science Publishers. Source

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