Article

V-ATPase inhibitors and implication in cancer treatment

{ "0" : "Entrerríos s/n, Santiago de Compostela C.P. 15782, Spain" , "1" : "Unidad de Medicina Molecular - Fundación Pública Galega de Medicina Xenómica, Edificio de Consultas planta -2, Hospital Clinico Universitario C.P. 15706, Santiago de Compostela, Spain" , "3" : "V-ATPase inhibitors" , "4" : "Tumor metastasis" , "5" : "Tumor cell growth" , "6" : "Chemoresistance" , "7" : "V-ATPases" , "8" : "Concanamycin" , "9" : "Bafilomycin" , "10" : "Salicylihalamide" , "11" : "Archazolid" , "12" : "Indolyls"}
Cancer Treatment Reviews (Impact Factor: 7.59). 12/2009; 35(8):707-713. DOI: 10.1016/j.ctrv.2009.08.003

ABSTRACT

Acidity is one of the main features of the tumors. The V-ATPase is the primary responsible for the control of tumor microenvironment by proton extrusion to the extracellular medium. The acid environment favors tissue damage, activation of destructive enzymes in the extracellular matrix, the acquisition of metastatic cell phenotypes as well as increasing the destructive capacity. The application of specific inhibitors of V-ATPases, can decrease the acidity of tumor and may allow the reduction of tumor metastasis, acting on the survival of tumor cells and prevent the phenomena of chemoresistance. Among the most important inhibitors can be distinguished benzolactone enamides (salicylihalamide), lobatamide A and B, apicularen, indolyls, oximidine, macrolactone archazolid, lobatamide C, and cruentaren. The latest generation of inhibitors includes NiK12192, FR202126, and PPI SB 242784. The purpose of this paper is to describe the latest advances in the field of V-ATPase inhibitors, describe further developments related to the classic inhibitors, and discuss new potential applications of these drugs in cancer treatment.

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    • "Archazolids are macrolides that have originally been isolated from the myxobacterium Archangium gephyra[30], and are available also by chemical synthesis[31,32]. Archazolids have attracted attention as highly potent V-ATPase inhibitors that exert promising anti-tumor effects1516171833343536. Because Notch signaling activation in part depends on endocytosis[10,11,37]and V-ATPase has therefore been linked with the Notch pathway[35,38], we hypothesized that V-ATPase inhibition might represent an alternative option to target leukemic cells. "
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    ABSTRACT: // Siwei Zhang 1 , Lina S. Schneider 1 , Binje Vick 2,4 , Michaela Grunert 2 , Irmela Jeremias 2,3,4 , Dirk Menche 5 , Rolf Müller 6 , Angelika M. Vollmar 1 and Johanna Liebl 1 1 Department of Pharmacy, Pharmaceutical Biology, Ludwig-Maximilians-University, Munich, Germany 2 Department of Gene Vectors, Helmholtz Zentrum München, German Research Center for Environmental Health, Munich, Germany 3 Department of Oncology/Hematology, Dr. von Haunersches Kinderspital, Munich, Germany 4 German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany 5 Kekulé-Institut für Organische Chemie und Biochemie der Universität Bonn, Bonn, Germany 6 Helmholtz Institute for Pharmaceutical Research Saarland, Helmholtz Centre for Infection Research and Department of Pharmaceutical Biotechnology, Saarland University, Saarbrücken, Germany Correspondence to: Johanna Liebl, email: // Keywords : Archazolid, leukemia, natural compounds Received : May 20, 2015 Accepted : October 07, 2015 Published : October 19, 2015 Abstract Prognosis for patients suffering from T-ALL is still very poor and new strategies for T-ALL treatment are urgently needed. Our study shows potent anti-leukemic effects of the myxobacterial V-ATPase inhibitor Archazolid A. Archazolid A reduced growth and potently induced death of leukemic cell lines and human leukemic samples. By inhibiting lysosomal acidification, Archazolid A blocked activation of the Notch pathway, however, this was not the mechanism of V-ATPase inhibition relevant for cell death induction. In fact, V-ATPase inhibition by Archazolid A decreased the anti-apoptotic protein survivin. As underlying mode of action, this work is in line with recent studies from our group demonstrating that Archazolid A induced S-phase cell cycle arrest by interfering with the iron metabolism in leukemic cells. Our study provides evidence for V-ATPase inhibition as a potential new therapeutic option for T-ALL.
    Full-text · Book · Oct 2015
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    • "Current antineoplastic strategies are aimed at promoting the efficiency and specificity of therapies for gastric cancer. The present study indicated that rabeprazole, a second-generation PPI, could efficaciously induce apoptosis in human gastric cancer cells by blocking the intracellular proton extrusion, thus supporting the idea of PPIs as a potential treatment for gastric cancer (16,17). Highly proliferative cancer cells produce a large amount of H+ generated by aerobic glycolysis, lactic acid production and proton extrusion, leading to a lower extracellular pH level compared with normal tissues (18,19). "
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    ABSTRACT: Intracellular proton extrusion in gastric cancer cells has been reported to promote cancer cell survival under acidic conditions via hydrogen/potassium adenosine triphosphatase (H(+)/K(+)-ATPase). Rabeprazole is a frequently used second-generation proton pump inhibitor (PPI) that irreversibly inactivates gastric H(+)/K(+)-ATPase. Therefore, we hypothesized that rabeprazole could reduce the viability of gastric cancer cells. In the present study, four human gastric cancer cell lines and one non-cancer gastric cell line were cultured. Cell viability, the α- and β-subunits of H(+)/K(+)-ATPase and cellular apoptosis were analyzed by dye exclusion assay, reverse transcription-polymerase chain reaction and annexin V-fluorescein isothiocyanate/propidium iodide staining, respectively. The expression level of total extracellular signal-regulated protein kinase 1/2 (ERK 1/2) and phosphorylated-ERK protein was detected by western blot analysis. Gastric cancer cell lines were more tolerant of the acidic culture media than non-cancer cells. Administration of rabeprazole led to a marked decrease in the viability of MKN-28 cells. Exposure to rabeprazole induced significant apoptosis in AGS cells. Rabeprazole completely inhibited the phosphorylation of ERK 1/2 in the MKN-28 cells, whereas the same effect was not observed in either the KATO III or MKN-45 cells. The ERK 1/2 inhibitor, PD98059, attenuated the viability of the AGS cells. A similar antiproliferative effect was observed in the rabeprazole treatment group. In addition, PD98059 and rabeprazole were able to efficaciously inhibit the phosphorylation of ERK 1/2 in the gastric cancer cells. Therefore, it was concluded that rabeprazole can attenuate the cell viability of human gastric cancer cells through inactivation of the ERK1/2 signaling pathway. The results of the present study demonstrate that rabeprazole inhibits the viability of gastric cancer cells in vitro and may serve as a novel antineoplastic agent.
    Full-text · Article · Oct 2014 · Oncology letters
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    • "Vacuolar ATPases pump protons out of the cytoplasm and into intracellular vesicles, such as lysosomes in an ATP dependent process (Horova et al., 2013) and these events are also altered in cancer (Perez-Sayans et al., 2009a,b). Importantly, the activity of these pumps is tightly coupled to endosome trafficking, suggesting that they need not be resident at the plasma membrane to exert their pH regulatory effects (Martinez-Zaguilan et al., 1999, 2013). "
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    ABSTRACT: Cells maintain intracellular pH (pHi) within a narrow range (7.1-7.2) by controlling membrane proton pumps and transporters whose activity is set by intra-cytoplasmic pH sensors. These sensors have the ability to recognize and induce cellular responses to maintain the pHi, often at the expense of acidifying the extracellular pH. In turn, extracellular acidification impacts cells via specific acid-sensing ion channels (ASICs) and proton-sensing G-protein coupled receptors (GPCRs). In this review, we will discuss some of the major players in proton sensing at the plasma membrane and their downstream consequences in cancer cells and how these pH-mediated changes affect processes such as migration and metastasis. The complex mechanisms by which they transduce acid pH signals to the cytoplasm and nucleus are not well understood. However, there is evidence that expression of proton-sensing GPCRs such as GPR4, TDAG8, and OGR1 can regulate aspects of tumorigenesis and invasion, including cofilin and talin regulated actin (de-)polymerization. Major mechanisms for maintenance of pHi homeostasis include monocarboxylate, bicarbonate, and proton transporters. Notably, there is little evidence suggesting a link between their activities and those of the extracellular H(+)-sensors, suggesting a mechanistic disconnect between intra- and extracellular pH. Understanding the mechanisms of pH sensing and regulation may lead to novel and informed therapeutic strategies that can target acidosis, a common physical hallmark of solid tumors.
    Full-text · Article · Dec 2013 · Frontiers in Physiology
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