Abstract
The natural product salicylihalamide is a potent inhibitor of the Vacuolar ATPase (V-ATPase), a potential target for antitumor chemotherapy. We generated salicylihalamide-resistant tumor cell lines typified by an overexpansion of lysosomal organelles. We also found that many tumor cell lines upregulate tissue-specific plasmalemmal V-ATPases, and hypothesize that tumors that derive their energy from glycolysis rely on these isoforms to maintain a neutral cytosolic pH. To further validate the potential of V-ATPase inhibitors as leads for cancer chemotherapy, we developed a multigram synthesis of the potent salicylihalamide analog saliphenylhalamide.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Amides / chemical synthesis*
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Amides / chemistry
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Amides / pharmacology*
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Antineoplastic Agents / chemical synthesis*
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Antineoplastic Agents / chemistry
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Antineoplastic Agents / pharmacology*
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Biological Products / chemical synthesis*
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Biological Products / chemistry
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Biological Products / pharmacology*
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Bridged Bicyclo Compounds, Heterocyclic / chemical synthesis*
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Bridged Bicyclo Compounds, Heterocyclic / chemistry
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Bridged Bicyclo Compounds, Heterocyclic / pharmacology*
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Drug Screening Assays, Antitumor
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Humans
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Molecular Structure
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Salicylates / chemical synthesis*
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Salicylates / chemistry
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Salicylates / pharmacology*
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Vacuolar Proton-Translocating ATPases / antagonists & inhibitors*
Substances
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Amides
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Antineoplastic Agents
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Biological Products
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Bridged Bicyclo Compounds, Heterocyclic
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Salicylates
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salicylihalamide A
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saliphenylhalamide
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Vacuolar Proton-Translocating ATPases