[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.

Publisher: Nature Publishing Group on behalf of Cancer Research UK Country of Publication: England NLM ID: 0370635 Publication Model: Print Cited Medium: Print ISSN: 0007-0920 (Print) Linking ISSN: 00070920 NLM ISO Abbreviation: Br J Cancer Subsets: MEDLINE

Publication: 2002- : London : Nature Publishing Group on behalf of Cancer Research UK
Original Publication: London, Lewis.

Apoptosis* ; Mitogen-Activated Protein Kinases*; Antineoplastic Agents/*pharmacology ; Calcium-Calmodulin-Dependent Protein Kinases/*metabolism ; Carcinoma, Small Cell/*drug therapy ; Lung Neoplasms/*drug therapy ; Oligopeptides/*pharmacology; 3T3 Cells ; Animals ; Carcinoma, Small Cell/pathology ; Cell Division/drug effects ; Dose-Response Relationship, Drug ; Edema/chemically induced ; Enzyme Activation/drug effects ; GTP-Binding Proteins/metabolism ; Humans ; JNK Mitogen-Activated Protein Kinases ; Lung Neoplasms/pathology ; Mice ; Neuropeptides/pharmacology ; Rabbits ; Reactive Oxygen Species/physiology ; Tumor Cells, Cultured

[Arg6,D-Trp7,9,NmePhe8]-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 (IC50 = 24.5 +/- 1.5 and 38.5 +/- 1.5 microM 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 (EC50 = 5.9 +/- 0.1 and 15.2 +/- 2.7 microM for the H69 and H510 cell lines respectively) and stimulates c-jun-N-terminal kinase (JNK) activity in SCLC cells (EC50 = 3.2 +/- 0.1 and 15.2 +/- 2.7 microM). 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 microM), 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.

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0 (Antineoplastic Agents)
0 (Neuropeptides)
0 (Oligopeptides)
0 (Reactive Oxygen Species)
115150-59-9 (arginyl-tryptophyl-N-methylphenylalanyl-tryptophyl-leucyl-methioninamide)
EC 2.7.11.17 (Calcium-Calmodulin-Dependent Protein Kinases)
EC 2.7.11.24 (JNK Mitogen-Activated Protein Kinases)
EC 2.7.11.24 (Mitogen-Activated Protein Kinases)
EC 3.6.1.- (GTP-Binding Proteins)

Date Created: 19990611 Date Completed: 19990624 Latest Revision: 20181113

20250114

PMC2363053

10.1038/sj.bjc.6690458

10362111