Lung Cancer pp 299-307 | Cite as

[D-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

  • Alison MacKinnon
  • Tariq Sethi
Part of the Methods in Molecular Medicine™ book series (MIMM, volume 74)


[D-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 (1,2). 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. Factors affecting the balance between SCLC cell proliferation and apoptosis will have a profound effect on tumor growth. However, the mechanisms which regulate apoptosis remain poorly understood. The p46/p54 c-jun N-terminal kinases (JNKs) are members of the MAPK family that activate the transcription factors c-jun and ATF2 and are stimulated by environmental stress (e.g., heat shock, UV, TNF-α), receptor tyrosine kinases and G-protein-linked receptors (3-5). Activation of JNK1 has been shown to be important for UV-induced apoptosis in SCLC cells (6). Reactive oxygen species (ROS) are involved in signaling events leading to apoptosis in many cell types (7). ROS have been shown to activate JNK (8), c-jun expression, and AP-1 activity (9,10). The role of ROS in pathways leading to programmed cell death is particularly pertinent in cancers where the oxygen tension at the center of tumors may be particularly low (11).


Small Cell Lung Cancer Myelin Basic Protein SITA Medium Small Cell Lung Cancer Cell H510 Cell Line 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


  1. 1.
    MacKinnon, A. C., Armstrong, R. A., Waters, C., Cummings, J., Smyth, J. F., Haslett, C., and Sethi, T. (1999) [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. Br. J. Cancer 80, 1026–1034.PubMedCrossRefGoogle Scholar
  2. 2.
    MacKinnon, A. C., Waters, C. M., Rahman, I., Harani, N., Rintoul, R., Haslett, C., and Sethi, T. (2000) [Arg6, D-Trp7,9, NmePhe8]-substance p (6-11) (antagonist G) induces induces AP-1 transcription and sensitises cells to chemotherapy. Br. J. Cancer 83, 941–948.PubMedCrossRefGoogle Scholar
  3. 3.
    Chen, Y., Meyer, C. F., and Tan, T. (1996) Persistant activation of c-jun N-terminal Kinase 1 (JNK1) in γ radiation-induced apoptosis. J. Biol. Chem. 271, 631–634.PubMedCrossRefGoogle Scholar
  4. 4.
    Verheij, M., Bose, R., Lin, X. H., Yao, B., Jarvis, W. D., Grant, S., et al. (1996) Requirement for ceramide-initiated SAPK/JNK signalling in stress-induced apoptosis. Nature 380, 75–79.PubMedCrossRefGoogle Scholar
  5. 5.
    Coso, O. A., Chiariello, M., Kalinec, G., Kyriakis, J. M., Woodgett, J., and Gutkind, J. S. (1995) Transforming G protein coupled receptors potently activate JNK (SAPK). J. Biol. Chem. 270 5620–5624.PubMedCrossRefGoogle Scholar
  6. 6.
    Butterfield, L., Storey, B., Maas, L., and Heasley, L. E. (1997) c-jun NH2-terminal kinase regulation of the apoptotic response of small cell lung cancer cells to ultraviolet radiation. J. Biol. Chem. 272, 10110–10116.PubMedCrossRefGoogle Scholar
  7. 7.
    Buttke, T. M. and Sandstrom, P. A. (1994) Oxidative stress as a mediator of apoptosis. Immunol. Today 15, 7–11.PubMedCrossRefGoogle Scholar
  8. 8.
    Laderoute, K. R. and Webster, K. A. (1997) Hypoxia/reoxygenation stimulates jun kinase activity through redox signalling in cardiac myocytes. Circ. Res. 80, 337–344.CrossRefGoogle Scholar
  9. 9.
    Janssen, Y. M. W., Matalon, S., and Mossman, B. T. (1997) Differential induction of c-fos, c-jun and apoptosis in lung epithelial cells exposed to ROS or RNS. Am. J. Physiol. 273, L789–L796.PubMedGoogle Scholar
  10. 10.
    Xu, Y., Bradham, C., Brenner, D. A., and Czaja, M. J. (1997) Hydrogen peroxide-induced liver cell necrosis is dependent on AP-1 activation. Am. J. Physiol. 273, G795–G803.PubMedGoogle Scholar
  11. 11.
    Bush, R. S., Jenkin, R. D. T., Allt, W. E. C., Beale, F. A., Bean, H., Dembo, A. J., and Pringle, J. F. (1978) Definitive evidence for hypoxic cells influencing cure in cancer therapy. Br. J. Cancer 37, 302–306.Google Scholar
  12. 12.
    Tallet, A., Chilvers, E. R., Hannah, S., Dransfield, I., Lawson, M. F., Haslett, C., and Sethi, T. (1996) Inhibition of neuropeptide-stimulated tyrosine phosphorylation and tyrosine kinase activity stimulates apoptosis in small cell lung cancer cells. Cancer Res. 56, 4255–4263.Google Scholar

Copyright information

© Humana Press Inc., Totowa, NJ 2003

Authors and Affiliations

  • Alison MacKinnon
    • 1
  • Tariq Sethi
    • 1
  1. 1.Rayne Laboratory, Centre for Inflammation Research, Respiratory Medicine UnitUniversity of Edinburgh Medical SchoolEdinburgh

Personalised recommendations