Repository logo
 

[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.

Published version
Peer-reviewed

Loading...
Thumbnail Image

Type

Article

Change log

Authors

MacKinnon, AC 
Waters, C 
Rahman, I 
Harani, N 

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.

Description

Keywords

Acetylcysteine, Animals, Antineoplastic Agents, Antineoplastic Agents, Phytogenic, Apoptosis, 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

Journal Title

Br J Cancer

Conference Name

Journal ISSN

0007-0920
1532-1827

Volume Title

83

Publisher

Springer Science and Business Media LLC