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: 6.02). 12/2009; 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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    ABSTRACT: Fighting metastasis is a major challenge in cancer therapy and novel therapeutic targets and drugs are highly appreciated. Resistance of invasive cells to anoikis, a particular type of apoptosis induced by loss of cell-matrix contact, is a major prerequisite for their metastatic spread. Inducing anoikis in metastatic cancer cells is therefore a promising therapeutic approach. The vacuolar-ATPase (V-ATPase), a proton pump located at the membrane of acidic organelles, has recently come to focus as an anti-metastatic cancer target. As V-ATPase inhibitors have shown to prevent invasion of tumor cells and are able to induce apoptosis we proposed that V-ATPase inhibition induces anoikis related pathways in invasive cancer cells. We used the V-ATPase inhibitor archazolid to investigate the mechanism of anoikis induction in various metastatic cancer cells (T24, MDA-MB-231, 4T1, 5637) in vitro. Anoikis induction by archazolid was characterized by decreased c-FLIP expression and caspase-8 activation as well as reduction of active integrin β1 and an early increase of the pro-apoptotic protein BIM. However, we observed that archazolid also induces mechanisms opposing anoikis such degradation of BIM mediated by ERK-, Akt- and Src-kinases at later time points and induction of reactive oxygen species. Still, intravenous injection of archazolid treated 4T1-Luc2 mouse breast cancer cells resulted in reduced metastasis in mice lungs. Thus, V-ATPase inhibition is not only an interesting option to reduce cancer metastasis but also to better understand anoikis resistance and to find choices to fight against it.
    Molecular Cancer Therapeutics 01/2014; · 5.60 Impact Factor
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    ABSTRACT: Much effort is currently devoted to developing patient-specific cancer therapy based on molecular characterization of tumors. In particular, this approach seeks to identify driver mutations that can be blocked through small molecular inhibitors. However, this approach is limited by extensive intratumoral genetic heterogeneity, and, not surprisingly, even dramatic initial responses are typically of limited duration as resistant tumor clones rapidly emerge and proliferate. We propose an alternative approach based on observations that while tumor evolution produces genetic divergence, it is also associated with striking phenotypic convergence that loosely correspond to the well-known cancer "hallmarks". These convergent properties can be described as driver phenotypes and may be more consistently and robustly expressed than genetic targets. To this purpose, it is necessary to identify strategies that are critical for cancer progression and metastases, and it is likely that these driver phenotypes will be closely related to cancer "hallmarks". It appears that an antiacidic approach, by targetting a driver phenotype in tumors, may be thought as a future strategy against tumors in either preventing the occurrence of cancer or treating tumor patients with multiple aims, including the improvement of efficacy of existing therapies, possibly reducing their systemic side effects, and controlling tumor growth, progression, and metastasis. This may be achieved with existing molecules such as proton pump inhibitors (PPIs) and buffers such as sodium bicarbonate, citrate, or TRIS.
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May 15, 2014