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. 2000 Sep 4;83(7):941–948. doi: 10.1054/bjoc.2000.1362

[Arg6, D-Trp7,9, NmePhe8]-substance P (6–11) (antagonist G) inducesP-1 transcription and sensitizes cells to chemotherapy

A C MacKinnon 1, C Waters 2, I Rahman 1, N Harani 1, R Rintoul 1, C Haslett 1, T Sethi 1
PMCID: PMC2374683  PMID: 10970698

Abstract

[Arg6, D-Trp7,9, NmePhe8]-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. © 2000 Cancer Research Campaign

Keywords: SCLC; [Arg6, D-Trp7,9, NmePhe8]-substance P (6–11); antagonist G; AP-1; apoptosis; ROS; chemosensitivity

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Selected References

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