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Vol. 297, Issue 1, 114-120, April 2001
Laboratory of Natural Products, Division of Basic Sciences,
National Cancer Institute, Frederick, Maryland (M.R.B., T.C.M.);
SmithKline Beecham SpA, Via Zambeletti, Milan, Italy (C.F., P.B.,
S.G.); Institute of Molecular and Cellular Biosciences, University of
Tokyo, Bunkyo-ku, Tokyo, Japan (J.W.K., Y.H.); SAIC Frederick,
Frederick, Maryland (J.A.B.); and Department of Biology, University of
California, Santa Cruz, California (B.J.B., E.J.B.)
A series of naturally occurring compounds reported recently by multiple
laboratories defines a new small-molecule class sharing a unique
benzolactone enamide core structure and diverse biological actions,
including inhibition of growth of tumor cells and oncogene-transformed cell lines. Here we show that representative members of this class, including salicylihalamide A, lobatamides A-F, and oximidines I and II
inhibit mammalian vacuolar-type (H+)-ATPases (V-ATPases)
with unprecedented selectivity. Data derived from the NCI 60-cell
antitumor screen critically predicted the V-ATPase molecular target,
while specific biochemical assays provided confirmation and further
illumination. The compounds potently blocked representative V-ATPases
from human kidney, liver, and osteoclastic giant-cell tumor of bone but
were essentially inactive against V-ATPases of Neurospora
crassa and Saccharomyces cerevisiae and other
membrane ATPases. Essential regulation of pH in cytoplasmic, intraorganellar, and local extracellular spaces is provided by V-ATPases, which are ubiquitously distributed among eukaryotic cells
and tissues. The most potent and selective V-ATPase inhibitors heretofore known were the bafilomycins and concanamycins, which do not
discriminate between mammalian and nonmammalian V-ATPases. Numerous
physiological processes are mediated by V-ATPases, and aberrant
V-ATPase functions are implicated in many different human diseases.
Previous efforts to develop therapeutic pharmacological modulators of
V-ATPases have been frustrated by a lack of synthetically tractable and
biologically selective leads. Therefore, availability of the unique
benzolactone enamide inhibitor class may enable further elucidation of
functional and architectural features of mammalian versus nonmammalian
V-ATPase isoforms and provide new opportunities for targeting
V-ATPase-mediated processes implicated in diverse pathophysiological
phenomena, including cancer.
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E. J. Bowman, L. A. Graham, T. H. Stevens, and B. J. Bowman The Bafilomycin/Concanamycin Binding Site in Subunit c of the V-ATPases from Neurospora crassa and Saccharomyces cerevisiae J. Biol. Chem., August 6, 2004; 279(32): 33131 - 33138. [Abstract] [Full Text] [PDF]
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X.-S. Xie, D. Padron, X. Liao, J. Wang, M. G. Roth, and J. K. De Brabander Salicylihalamide A Inhibits the V0 Sector of the V-ATPase through a Mechanism Distinct from Bafilomycin A1 J. Biol. Chem., May 7, 2004; 279(19): 19755 - 19763. [Abstract] [Full Text] [PDF]
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E. J. Bowman, K. R. Gustafson, B. J. Bowman, and M. R. Boyd Identification of a New Chondropsin Class of Antitumor Compound That Selectively Inhibits V-ATPases J. Biol. Chem., November 7, 2003; 278(45): 44147 - 44152. [Abstract] [Full Text] [PDF]
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