| Summary: | 碩士 === 國立臺灣大學 === 藥學研究所 === 89 === I. The apoptotic activity of tryptanthrin derivatives in MCF7 cells
Tryptanthrin, indolo[2,1-b]quinazolin-6,12-dione, is a coplanar four-fused ring compound which contains N-phenyl-quinazoline skeleton similar to 2-phenyl-naphthalene. It was illustrated that compounds containing coplanar 2-phenyl-naphthalene skeleton exhibit different biological activites, while the bioactivities would be decreased or lost in unplanar structures. For example, batracylin, containing 2-phenyl-quinolone skeleton,inhibits the growth of carcinoma cell lines. In previous data, tryptanthrin derivatives with different substituents exert different potency of various bioactivities. It draws our attention to screen tryptanthrin derivatives for cytotoxicity and study their apoptotic activity as potential anticancer agents. In the cytotoxic assay, tryptanthrin derivatives, DQ181, DQ166 and EY093, exert cytotoxic activity in cancer cell lines including MCF7, HeLa, A498, SKOV3 cells. Our data showed that cells undergo apoptosis and die. MCF7 cells are the most sensitive to these tryptanthrin derivatives. DQ181 is the most potent compound of those tryptanthrin derivatives. The result suggested that DQ181 may be a new compound developed to treat breast cancer. We further study the mechanism of apoptosis induced by DQ181. The extensive experiments indicated DQ181-induced apoptosis may be via upregulation of the expression of Fas receptor and Fas ligand, resulting in activating caspase-8 mediated pathway.
Fas receptor protein overexpresses in two hours but decrease later. Fas ligand protein expression stimulated by DQ181 was elevated in a time dependent manner。
II. Inhibition of TCDD-induced aryl hydrocarbon receptor
translocation by tryptanthrin derivative DQ181
2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) and related compounds induce a broad spectrum of biochemical and toxic responses including carcinogenesis. Binding of TCDD to Ah receptor is followed by AhR transport to the nucleus, dimerization with the aryl hydrocarbon nuclear translocator (ARNT), and transcription of a potentially large number of genes containing AhR complex-binding sequences in their promoter regions. Genes encoding cytochrome P450s(CYPs) enzymes are regarded as AhR-regulated genes. Induction of cytochrome P1A1 mRNA is a sensitive marker of AhR—ligand interaction. Our result demonstrates that tryptanthrin derivative DQ181 can inhibit TCDD-induced cytochrome P1A1 mRNA expression regarding to blocking or stablizing AhR-Hsp90 complex followed by inhibition of translocation from cytosol to nuclear. It may interfere with cytochrome P450 1A1-related carcinogenesis.
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