Cytotoxic mechanisms of Cardiotoxin III (CTX III)、N′-(11H-indolo[3,2-c]quinolin-6-yl)-N,N-dimethylethane-1,2-diamine (IQDMA) and Naphtho[1,2-b]furan-4,5-dione (NFD)

• Main Authors: Ching-Ming Chien, 簡啟民
• Other Authors: Shinne-Ren Lin
• Format: Others
• Language: zh-TW
• Published: 2010
• Online Access: http://ndltd.ncl.edu.tw/handle/85029628380595944153

博士 === 高雄醫學大學 === 醫藥暨應用化學研究所 === 98 === Apoptosis plays an important role in the regulation of cellular activities in eukaryotes. Three predominant apoptotic pathways are the mitochondria-mediated intrinsic pathway, the death receptor-induced extrinsic pathway and apoptotic signalling evoked by endoplasmic reticulum (ER) stress. Three type of compounds (CTX III, IQDMA and NFD)-induced apoptotic cell death accompanied by regulation of Bcl-2 family, loss of mitochondrial membrane potential, release of cytochrome c and caspase-9, -3 activation. In addition, CTX III induced ER stress, release of Ca2+ ion, activation of calpain and caspase-12. Finally, cell death caused by both mtiochridal and ER stress dependent apoptosis. Cell cycle control is the major regulatory mechanism of cell growth. Many cytotoxic agents and/or DNA damaging agents arrest the cell cycle at the G1, S or G2/M phase and then induce apoptotic cell death. CTX III resulted in S phase arrest in the cell cycle progression, which was associated with a marked decrease expressions of cyclin A, cyclin B1, and CDK 1. Mitogen-activated protein kinase (MAPK) members have been identified as an important signaling in the control of cell proliferation and differentiation. The activation of JNK played an important role in CTX III induced apoptosis. Signal transducer and activator of transcription (STAT) proteins have been shown to have a major role in survival, proliferation, angiogenesis, and immune evasion of tumors. Inhibitions of phosphorylation of STAT3 and STAT5 with CTX III treatment and of STAT5 with IQDMA treatment regulated the downstream effects and linked to anti-proliferation. Tyrosine kinases, classified into receptor tyrosine kinases and non receptor kinases, play important role in regulation of cell proliferation, differentiation, survival, and carcinogenesis. CTX III inhibited phosphorylation of Src and then phosphorylation of EGFR at Y845 site, subsequently, cell cycle arrested at S phase. IQDMA abolished Src and STAT5 activation, later induced apoptosis. NFD treatment inactivated EGFR and PI3K/Akt pathway, leading to apoptotic death. Collectively, the study used three types of compounds for apoptosis and cell cycle arrest. These results provide the impetus for developing new therapeutic strategies in which synthetic compounds.