Sulfasalazine-induced reduction of glutathione levels in breast cancer cells: enhancement of growth-inhibitory activity of Doxorubicin

Chemotherapy. 2007;53(3):210-7. doi: 10.1159/000100812. Epub 2007 Mar 15.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B / antagonists & inhibitors
  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / antagonists & inhibitors
  • ATP-Binding Cassette Sub-Family B Member 4
  • Anti-Inflammatory Agents, Non-Steroidal / pharmacology*
  • Antibiotics, Antineoplastic / pharmacology*
  • Antimetabolites, Antineoplastic / metabolism
  • Breast Neoplasms / drug therapy*
  • Carcinoma / drug therapy
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Doxorubicin / pharmacology*
  • Drug Resistance, Neoplasm
  • Drug Synergism
  • Glutathione / analysis
  • Glutathione / metabolism
  • Humans
  • Methotrexate / metabolism
  • Oxidation-Reduction
  • Propionates / pharmacology
  • Quinolines / pharmacology
  • Sulfasalazine / pharmacology*
  • Tumor Stem Cell Assay

Substances

  • ATP Binding Cassette Transporter, Subfamily B
  • ATP Binding Cassette Transporter, Subfamily B, Member 1
  • Anti-Inflammatory Agents, Non-Steroidal
  • Antibiotics, Antineoplastic
  • Antimetabolites, Antineoplastic
  • Propionates
  • Quinolines
  • Sulfasalazine
  • verlukast
  • Doxorubicin
  • Glutathione
  • Methotrexate