Abstract
The selective modulation of ATP-binding cassette (ABC) efflux pumps overexpressed in multidrug resistant cancers (MDR) and attendant resensitization to chemotherapeutic agents represent a promising strategy for treating cancer. We have synthesized four novel pentacyclic Strychnos alkaloids alstolucines B (2), F (3), and A (5) and N-demethylalstogucine (4), in addition to known Strychnos alkaloid echitamidine (16), and we evaluated compounds 1-5 in biochemical assays with ABCC10 and P-glycoprotein (P-gp). Alstolucines B (2) and F (3) inhibited ABCC10 ATPase activity at 12.5 μM without affecting P-gp function; moreover, they resensitized ABCC10-transfected cell lines to paclitaxel at 10 μM. Altogether, the alstolucines represent promising lead candidates in the development of modulators of ABCC10 for MDR cancers overexpressing this pump.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, Non-P.H.S.
MeSH terms
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Adenosine Triphosphatases / antagonists & inhibitors
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Alkaloids / chemical synthesis*
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Alkaloids / pharmacology*
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Antineoplastic Agents, Phytogenic / pharmacology
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Cell Proliferation / drug effects*
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Drug Resistance, Multiple / drug effects*
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Drug Resistance, Neoplasm / drug effects*
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Enzyme Inhibitors / chemical synthesis
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Enzyme Inhibitors / pharmacology
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HEK293 Cells
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Humans
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Indole Alkaloids / chemical synthesis*
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Indole Alkaloids / pharmacology*
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Multidrug Resistance-Associated Proteins / antagonists & inhibitors*
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Paclitaxel / pharmacology
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Strychnos / chemistry*
Substances
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ABCC10 protein, human
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Alkaloids
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Antineoplastic Agents, Phytogenic
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Enzyme Inhibitors
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Indole Alkaloids
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Multidrug Resistance-Associated Proteins
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alstolucine B
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alstolucine F
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Adenosine Triphosphatases
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Paclitaxel