Cisplatin generates oxidative stress which is accompanied by rapid shifts in central carbon metabolism

Sci Rep. 2018 Mar 9;8(1):4306. doi: 10.1038/s41598-018-22640-y.


Cisplatin is commonly utilized in the treatment of solid tumors. Its mechanism of action is complex and multiple mechanisms of resistance have been described. We sought to determine the impact of cisplatin-generated oxidative stress on head and neck squamous cell carcinoma (HNSCC) proliferation, survival and metabolic activity in order to identify a potential metabolic signature associated with cisplatin response. DNA-bound cisplatin represents a small fraction of total intra-cellular cisplatin but generates a robust oxidative stress response. Neutralization of oxidative stress reverses cisplatin toxicity independent of the mechanism of cell death and TP53 mutational status. Cisplatin-induced oxidative stress triggers rapid shifts in carbon flux in 3 commonly utilized catabolic pathways: glycolysis, pentose phosphate pathway and citric acid cycle. Among these metabolic shifts, decreased flux from pyruvate into lactate is the only metabolic effect consistently observed across multiple HNSCC cell lines of varying genomic backgrounds and may reflect differential cisplatin sensitivity. Oxidative stress is a critical component of cisplatin cytotoxicity in HNSCC and is reflected in acute changes in carbon flux from pyruvate into lactate. This suggests that lactate may contribute to a metabolic signature of acute cisplatin toxicity, and could prove useful in optimizing cisplatin-based treatment regimens in HNSCC.

Publication types

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

MeSH terms

  • Animals
  • Antineoplastic Agents / pharmacology*
  • Carbon / metabolism*
  • Carcinoma, Squamous Cell / metabolism*
  • Cell Line, Tumor
  • Cisplatin / pharmacology*
  • Citric Acid Cycle
  • Female
  • Glycolysis
  • Head and Neck Neoplasms / metabolism*
  • Humans
  • Lactic Acid / metabolism
  • Mice
  • Mice, Nude
  • Oxidative Stress / drug effects*
  • Pentose Phosphate Pathway
  • Pyruvic Acid / metabolism
  • Tumor Suppressor Protein p53 / genetics


  • Antineoplastic Agents
  • Tumor Suppressor Protein p53
  • Lactic Acid
  • Carbon
  • Pyruvic Acid
  • Cisplatin