| Summary: | 碩士 === 臺北醫學大學 === 生藥學研究所 === 91 === Cancer is one of the major leading causes of human death, however no effective anti-cancer drug was developed. In this study, nine flavones and eight flavanones derivatives were used to examine their apoptotic activities and mechanism in three human colorectal carcinoma cells with different p53 status including HT29 and COLO 320HSR (p53 mut/mut) and COLO205 (p53 wt/wt). Among these tested compounds, flavone, and 2’-hydroxyflavanone (2’-OH flavanone) showed the significant cytotoxicity on cells by MTT assays, accompanied by a dose- and time- dependent occurrence of characteristics of apoptosis including appearances of DNA fragmentation, apoptotic bodies and hypodiploid cells. P21 protein were induced in flavone- and 2’-OH flavanone-treated cells, however p53 protein remained unchanged. Cleavage of caspase 3 substrates, poly-(ADP-ribose) polymerase (PARP), and a transient activation of caspase 3, but not caspase 1, activity appeared in flavone-, and 2’-OH flavanone-treated COLO205 and HT29 cells. Apoptosis induced by indicated flavonoids was also attenuated by caspase 3 inhibitor z-DEVD-FMK, but not caspase 1 inhibitor z-YVAD-FMK. An increase in endogenous ROS production was detected in flavone- or 2’-OH flavanone-treated colorectal carcinoma cells by DCHF-DA assay. Antioxidants such as tiron, catalase, superoxide dismutase and pyrrolidine dithiocarbamate, but not diphenylene iodonium, significantly inhibit flavone- or 2’-OH flavanone -induced apoptosis. Additionally, a decrease in anti-apoptotic protein Mcl-1 and Bcl-xL were found in flavone-, and 2’-OH flavanone-treated colorectal carcinoma cells, whereas Bcl-2, Bax, Bad and Bag proteins remained unchanged. In nude mice anti-tumoral animal model, flavone and 2’-OH flavanone exhibited the antitumor effects in nude mice with COLO 205 tumor xenografts. Results of the in vitro and in vivo study, apoptosis induced by flavone and 2’-OH flavanone in colon carcinoma cells were through ROS production, p21 and caspase 3 cascades are involved in the apoptotic mechanisms.
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