[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
[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).
KeywordsSmall Cell Lung Cancer Myelin Basic Protein SITA Medium Small Cell Lung Cancer Cell H510 Cell Line
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