[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

[Arg(6), D-Trp(7,9), N(me)Phe(8)]-substance P (6-11) (antagonist G) inhibit s small cell lung cancer (SCLC) growth and is entering Phase II clinical in vestigation 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 tha t the stimulation of JNK and apoptosis by antagonist G is dependent upon th e generation of reactive oxygen species (ROS) being inhibited either by ano xia or the presence of N-acetyl cysteine (n-AC). Antagonist G is not intrin sically 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, an tagonist G reduces cellular glutathione (GSH) levels (38% reduction) and st imulates ceramide production and lipid peroxidation (112% increase). At pla sma concentrations achieved clinically in the phase I studies, antagonist G augments, more than additively, growth inhibition induced by etoposide. Ou r results suggest that antagonist G may be particularly effective as an add itional treatment with standard chemotherapy in SCLC. These novel findings will be important for the clinical application of this new and exciting com pound and for the future drug development of new agents to treat this aggre ssive cancer. (C) 2000 Cancer Research Campaign.