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. 1999 Jun;80(7):1026–1034. doi: 10.1038/sj.bjc.6690458

[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

A C MacKinnon 1, R A Armstrong 2, C M Waters 3, J Cummings 3, J F Smyth 3, C Haslett 1, T Sethi 1
PMCID: PMC2363053  PMID: 10362111

Abstract

[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 μM 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 μM 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 μM). 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 μM), 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. © 1999 Cancer Research Campaign

Keywords: antagonist G, SCLC, JNK, apoptosis, G-protein, neuropeptide

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Selected References

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