[Arg(6), D-Trp(7,9), N(me)Phe(8)]-substance P (6-11) (antagonist G) induces AP-1 transcription and sensitizes cells to chemotherapy

Alison C MacKinnon, C Waters, Irfan Rahman, N Harani, R Rintoul, Christopher Haslett, Tariq Sethi

Research output: Contribution to journalArticlepeer-review

Abstract

[Arg(6), D-Trp(7,9), N(me)Phe(8)]-substance P (6-11) (antagonist G) inhibits small cell lung cancer (SCLC) growth and is entering Phase II clinical investigation for the treatment of SCLC. As well as acting as a neuropeptide receptor antagonist, antagonist G stimulates c-jun-N-terminal kinase (JNK) activity and apoptosis in SCLC cells. We extend these findings and show that the stimulation of JNK and apoptosis by antagonist G is dependent upon the generation of reactive oxygen species (ROS) being inhibited either by anoxia or the presence of N-acetyl cysteine (n-AC). Antagonist G is not intrinsically a free radical oxygen donor but stimulates free radical generation specifically within SCLC cells (6.2-fold) and increases the activity of the redox-sensitive transcription factor AP-1 by 61%. In keeping with this, antagonist G reduces cellular glutathione (GSH) levels (38% reduction) and stimulates ceramide production and lipid peroxidation (112% increase). At plasma concentrations achieved clinically in the phase I studies, antagonist G augments, more than additively, growth inhibition induced by etoposide. Our results suggest that antagonist G may be particularly effective as an additional treatment with standard chemotherapy in SCLC. These novel findings will be important for the clinical application of this new and exciting compound and for the future drug development of new agents to treat this aggressive cancer.
Original languageEnglish
Pages (from-to)941-8
Number of pages8
JournalBritish Journal of Cancer
Volume83
Issue number7
DOIs
Publication statusPublished - Oct 2000

Keywords

  • Acetylcysteine/pharmacology
  • Animals
  • Antineoplastic Agents
  • Antineoplastic Agents, Phytogenic
  • Apoptosis/drug effects
  • CHO Cells
  • Carcinoma, Small Cell
  • Cell Division
  • Cricetinae
  • Drug Synergism
  • Etoposide
  • Free Radical Scavengers
  • Glutathione
  • Growth Inhibitors
  • JNK Mitogen-Activated Protein Kinases
  • Lipid Peroxidation
  • Lung Neoplasms
  • MAP Kinase Kinase 4
  • Mitogen-Activated Protein Kinase Kinases
  • Oligopeptides
  • Oxidation-Reduction
  • Reactive Oxygen Species
  • Stimulation, Chemical
  • Transcription Factor AP-1
  • Transcription, Genetic
  • Tumor Cells, Cultured

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