Abstract
Background:
We previously showed that the anti-inflammatory drug, sulfasalazine (salicylazosulfapyridine, SASP), can arrest proliferation of MCF-7 and MDA-MB-231 mammary cancer cells by inhibiting uptake of cystine via the x(c-) cystine/glutamate antiporter. Here we examined SASP with regard to reduction of cellular glutathione (GSH) levels and drug efficacy-enhancing ability.
Methods:
GSH levels were measured spectrophotometrically. Cellular drug retention was determined with 3H-labeled methotrexate, and drug efficacy with a colony formation assay.
Results:
Incubation of the mammary cancer cells with SASP (0.3-0.5 mM) led to reduction of their GSH content in a time- and concentration-dependent manner. Similar to MK-571, a multidrug resistance-associated protein inhibitor, SASP increased intracellular accumulation of methotrexate. Preincubation of cells with SASP (0.3 mM) significantly enhanced the potency of the anticancer agent doxorubicin (2.5 nM).
Conclusions:
SASP-induced reduction of cellular GSH levels can lead to growth arrest of mammary cancer cells and enhancement of anticancer drug efficacy.
Copyright 2007 S. Karger AG, Basel.
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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ATP Binding Cassette Transporter, Subfamily B / antagonists & inhibitors
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ATP Binding Cassette Transporter, Subfamily B, Member 1 / antagonists & inhibitors
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ATP-Binding Cassette Sub-Family B Member 4
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Anti-Inflammatory Agents, Non-Steroidal / pharmacology*
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Antibiotics, Antineoplastic / pharmacology*
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Antimetabolites, Antineoplastic / metabolism
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Breast Neoplasms / drug therapy*
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Carcinoma / drug therapy
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Cell Line, Tumor
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Cell Proliferation / drug effects
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Doxorubicin / pharmacology*
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Drug Resistance, Neoplasm
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Drug Synergism
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Glutathione / analysis
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Glutathione / metabolism
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Humans
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Methotrexate / metabolism
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Oxidation-Reduction
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Propionates / pharmacology
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Quinolines / pharmacology
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Sulfasalazine / pharmacology*
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Tumor Stem Cell Assay
Substances
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ATP Binding Cassette Transporter, Subfamily B
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ATP Binding Cassette Transporter, Subfamily B, Member 1
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Anti-Inflammatory Agents, Non-Steroidal
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Antibiotics, Antineoplastic
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Antimetabolites, Antineoplastic
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Propionates
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Quinolines
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Sulfasalazine
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verlukast
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Doxorubicin
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Glutathione
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Methotrexate