Inhibition of glutathione synthesis reverses Bcl-2-mediated cisplatin resistance

Charles M Rudin, Zejia Yang, Lisa M Schumaker, David J VanderWeele, Kenneth Newkirk, Merrill J Egorin, Eleanor G Zuhowski, Kevin J Cullen

Research output: Contribution to journalArticlepeer-review

160 Scopus citations


Cisplatin is a potent cytotoxic agent that functions as a bivalent electrophile, forming both interstrand and intrastrand DNA cross-links. Cisplatin-mediated DNA damage results in cell cycle arrest and initiation of apoptotic cell death. Increased cellular glutathione concentrations have been closely correlated with cisplatin resistance but do not reduce the extent of cisplatin-DNA adduct formation. One hypothesis to explain the ability of glutathione to inhibit cisplatin cytotoxicity is that glutathione, through its antioxidant function, plays a role in apoptotic regulatory pathways. We tested this hypothesis using MCF-7 breast cancer cells transfected with the apoptotic inhibitor Bcl-2. Bcl-2 overexpression in MCF-7 cells was associated with a nearly 3-fold increase in cellular glutathione levels and with increased resistance to cell death after cisplatin exposure. Treatment of MCF-7 lines with buthionine sulfoximine, an inhibitor of glutathione synthesis, normalized glutathione levels in Bcl-2 and control transfectants and completely abrogated Bcl-2-mediated cisplatin resistance without affecting Bcl-2 expression. Bcl-2 overexpression and up-regulation of glutathione were not associated with a change in either cisplatin-DNA adduct formation or repair over time. These results suggest that Bcl-2-mediated cisplatin resistance in MCF-7 cells is dependent on up-regulation of glutathione production, which contributes to cell survival by mechanisms independent of cisplatin inactivation or inhibition of DNA adduct formation. A similar dependence on glutathione for Bcl-2-mediated inhibition of cisplatin toxicity was confirmed in a second cell line, the lymphocytic precursor FL5.12. Taken together, these data suggest that apoptotic signaling after genotoxic exposure can be inhibited by the antioxidant activity of glutathione. Inhibition of glutathione synthesis or modulation of glutathione stores in tumors that overexpress Bcl-2 may comprise a novel anticancer strategy.

Original languageEnglish (US)
Pages (from-to)312-8
Number of pages7
JournalCancer Research
Issue number2
StatePublished - Jan 15 2003


  • Antineoplastic Agents/pharmacology
  • Breast Neoplasms/drug therapy
  • Cisplatin/pharmacology
  • DNA Damage
  • DNA, Neoplasm/metabolism
  • Drug Resistance, Neoplasm
  • Gene Expression Regulation, Enzymologic
  • Gene Expression Regulation, Neoplastic
  • Glutamate-Cysteine Ligase/biosynthesis
  • Glutathione/antagonists & inhibitors
  • Glutathione Synthase/biosynthesis
  • Humans
  • Proto-Oncogene Proteins c-bcl-2/biosynthesis
  • Transfection
  • Tumor Cells, Cultured
  • Up-Regulation
  • gamma-Glutamyltransferase/biosynthesis


Dive into the research topics of 'Inhibition of glutathione synthesis reverses Bcl-2-mediated cisplatin resistance'. Together they form a unique fingerprint.

Cite this