[Arg6,D-Trp7,9,NmePhe8]-substance P (6–11) activates JNK and induces apoptosis in small cell lung cancer cells via an oxidant-dependent mechanism

• Published in: British journal of cancer 1999-06, Vol.80 (7), p.1026-1034
• Main Authors: MacKinnon, A C, Armstrong, R A, Waters, C M, Cummings, J, Smyth, J F, Haslett, C, Sethi, T
• Format: Article
• Language: English
• Subjects: 3T3 Cells; Animals; Antineoplastic agents; Antineoplastic Agents - pharmacology; Apoptosis; Biological and medical sciences; Biomedical and Life Sciences; Biomedicine; Calcium-Calmodulin-Dependent Protein Kinases - metabolism; Cancer Research; Carcinoma, Small Cell - drug therapy; Carcinoma, Small Cell - pathology; Cell Division - drug effects; Chemotherapy; Dose-Response Relationship, Drug; Drug Resistance; Edema - chemically induced; Enzyme Activation - drug effects; Epidemiology; GTP-Binding Proteins - metabolism; Humans; JNK Mitogen-Activated Protein Kinases; Lung Neoplasms - drug therapy; Lung Neoplasms - pathology; Medical sciences; Mice; Mitogen-Activated Protein Kinases; Molecular Medicine; Neuropeptides - pharmacology; Oligopeptides - pharmacology; Oncology; Pharmacology. Drug treatments; Rabbits; Reactive Oxygen Species - physiology; Regular; regular-article; Tumor Cells, Cultured
• ISSN: 0007-0920; 1532-1827
• DOI: 10.1038/sj.bjc.6690458

Summary [Arg 6 ,D-Trp 7,9 ,N me Phe 8 ]-substance P (6–11) (antagonist G) is a novel class of anti-cancer agent that inhibits small-cell lung cancer (SCLC) cell growth in vitro and in vivo and is entering phase II clinical investigation for the treatment of SCLC. Although antagonist G blocks SCLC cell growth (IC 50 = 24.5 ± 1.5 and 38.5 ± 1.5 μ M for the H69 and H510 cell lines respectively), its exact mechanism of action is unclear. This study shows that antagonist G stimulates apoptosis as assessed by morphology (EC 50 = 5.9 ± 0.1 and 15.2 ± 2.7 μ M for the H69 and H510 cell lines respectively) and stimulates c- jun -N-terminal kinase (JNK) activity in SCLC cells (EC 50 = 3.2 ± 0.1 and 15.2 ± 2.7 μ M ). This activity is neuropeptide-independent, but dependent on the generation of reactive oxygen species (ROS) and is inhibited by the free radical scavenger n-acetyl cysteine. Furthermore, antagonist G itself induces inflammation (59% increase in oedema volume compared to control) and potentiates (by 35–40%) bradykinin-induced oedema formation in vivo. In view of these results we show that, as well as acting as a ‘broad-spectrum’ neuropeptide antagonist, antagonist G stimulates basal G-protein activity in SCLC cell membranes (81 ± 12% stimulation at 10 μ M ), thereby displaying a unique ability to stimulate certain signal transduction pathways by activating G-proteins. This novel activity may be instrumental for full anti-cancer activity in SCLC cells and may also account for antagonist G activity in non-neuropeptide-dependent cancers.