Sulfasalazine-induced reduction of glutathione levels in breast cancer cells: enhancement of growth-inhibitory activity of Doxorubicin.
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.
Narang
Vishal S
VS
College of Pharmacy, University of Cincinnati, Cincinnati, Ohio, USA.
Pauletti
Giovanni M
GM
Gout
Peter W
PW
Buckley
Donna J
DJ
Buckley
Arthur R
AR
D018435:ATP Binding Cassette Transporter, Subfamily B / Q000037:antagonists & inhibitors; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D000964:Antimetabolites, Antineoplastic / Q000378:metabolism; D001943:Breast Neoplasms / Q000188:drug therapy*; D002277:Carcinoma / Q000188:drug therapy; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004317:Doxorubicin / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm; D004357:Drug Synergism; D005978:Glutathione / Q000032:analysis / Q000378:metabolism; D006801:Humans; D008727:Methotrexate / Q000378:metabolism; D010084:Oxidation-Reduction; D011422:Propionates / Q000494:pharmacology; D011804:Quinolines / Q000494:pharmacology; D012460:Sulfasalazine / Q000494:pharmacology*; D014410:Tumor Stem Cell Assay; D000097202:ATP-Binding Cassette Sub-Family B Member 4
D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000894:Anti-Inflammatory Agents, Non-Steroidal; D000903:Antibiotics, Antineoplastic; D000964:Antimetabolites, Antineoplastic; D004317:Doxorubicin; D005978:Glutathione; D008727:Methotrexate; D011422:Propionates; D011804:Quinolines; D012460:Sulfasalazine; D000097202:ATP-Binding Cassette Sub-Family B Member 4; C059141:verlukast