Osteoclastic bone resorption can be completely abolished by inhibiting the vacuolar H(+)-ATPase (V-ATPase), a proton pump composed of at least 12 different subunits. However, V-ATPases are ubiquitous and it is unclear whether the osteoclast V-ATPase has a unique composition that would allow its selective inhibition. Aiming to answer this question, we compared human osteoclasts and monocytic THP.1 cells with respect to the localization of the a3 isoform of the 116-kDa subunit, which is indispensable for bone resorption, and sensitivity to SB242784, a V-ATPase inhibitor that prevents experimentally induced osteoporosis. By immunofluorescence, a3 was essentially nondetectable in THP.1 cells, while in osteoclasts a3 was highly upregulated and localized to lysosomes in nonresorbing osteoclasts. We isolated the lysosomal compartment from both sources as latex bead-containing phagolysosomes and compared them. Osteoclast phagolysosomes and THP.1 phagolysosomes both contained a3 and a1; however, the a3/a1 ratio was 3.8- to 11.2-fold higher in osteoclast phagolysosomes. Importantly, the V-ATPase-dependent acidification of phagolysosomes from both sources was essentially equally sensitive to SB242784. Thus, we observed no indication of a qualitative uniqueness of the osteoclast V-ATPase; rather, the high a3-level in osteoclasts may represent an upregulation of the common lysosomal V-ATPase. Our results, together with the reported phenotype of a3 deficiency and the reported efficacy of SB242784 in vivo, suggest that V-ATPase structure-independent mechanisms render bone resorption more sensitive than lysosomal function to V-ATPase inhibition. One such mechanism may be compensation of a3 by a1, which may be sufficient for retaining lysosomal function but not bone resorption.

2009-12-01·Cancer Treatment Reviews1区 · 医学

V-ATPase inhibitors and implication in cancer treatment

1区 · 医学

Review

作者: José Manuel Somoza-Martín ; Abel García-García ; Mario Pérez-Sayáns ; José Manuel Gándara Rey ; Francisco Barros-Angueira

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.

2008-04-01·Journal of Peptide Science4区 · 生物学

Membrane‐bound peptides from V‐ATPase subunit a do not interact with an indole‐type inhibitor

4区 · 生物学

Article

作者: Renske W. Hesselink ; Alexander Fedorov ; Manuel Prieto ; Marcus A. Hemminga

AbstractThe V‐ATPases are ATP‐dependent proton pumps, found in virtually all cells, responsible for acidification of organelles and energizing of plasma membranes. Its role in diseases, such as osteoporosis and metastatic cancer, makes the V‐ATPase a potential drug target. Short synthetic peptides that are presented here mimic the 7th transmembrane domain (TM7) of subunit a (Vph1p) of Saccharomyces cerevisiae V‐ATPase, an essential part of the membrane‐bound VO domain, where proton translocation takes place. The peptides adopt a transmembrane configuration only in membranes containing anionic lipids, stressing the importance of strong interfacial anchoring by the flanking lysines. Peptide P1, which contains the essential arginine R735, is monomeric, whereas peptide P2, which lacks this extra charge, tends to aggregate in the membrane. SB 242784, which is a highly potent inhibitor of V‐ATPase, does not show any interaction with the peptides, indicating that TM7 alone is not sufficient for inhibitor binding. Copyright © 2007 European Peptide Society and John Wiley & Sons, Ltd.

100 项与 SB-242784 相关的药物交易

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