| 摘要 |
The present invention relates to an isoxazole derivative, the compound of formula (I) herein after referred to as GIT27-NO, which is the NO-donating structurally modified form of (S,R)-3-phenyl-4,5-dihydro-5-isoxasole acetic acid, herein after referred to as VGX-1027. Treatment of three tumor cell li nes, rat astrocytoma C6, mouse fibrosarcoma L929, and mouse melanoma B16 cel ls with GIT27-NO resulted in a significant reduction of cell respiration and of number of viable cells, while VGX-1027 was completely ineffective. Hemog lobin, which act as NO-scavenger, restored cell viability, thus indicating t he NO-mediated tumoricidal effect of compound (I). GIT27-NO triggered apopto tic cell death in L929 cell cultures, while autophagic cell death is mainly responsible for the diminished viability of C6 and B16 cells. Moreover, GIT2 7-NO induced the production of reactive oxygen species which can be neutrali zed by antioxidant N-acetyl cysteine (NAC), indicating that reactive oxygen species (ROS) are at least partly involved in the reduction of cell viabilit y. The anti-tumor activity of GIT27-NO is mediated through activation of MAP kinases (ERK1/2, p38 and JNK) in cell-specific manner. The role of MAP kina ses was further confirmed by specific inhibitors of these molecules, PD98059 , SB202190, and SP600125. Finally, in vivo treatment with GIT27-NO significa ntly reduced tumor growth in syngeneic C57BL/6 mice implanted with B16 melan oma.
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