Semi-synthesized derivatives of diosgenin glycosides inhibit cell growth through estrogen receptor signaling pathway and induce apoptosis in MCF-7 breast adenocarcinoma

Estrogen receptor;Apoptosis;MCF-7 human breast adenocarcinoma;ER signaling pathway;Akt pathway

약학대학 제약학과 ;

University:서울대학교 대학원

关键词: Estrogen receptor;    Apoptosis;    MCF-7 human breast adenocarcinoma;    ER signaling pathway;    Akt pathway;   

Others  :  http://s-space.snu.ac.kr/bitstream/10371/133426/1/000000004975.pdf

美国|英语

来源: Seoul National University Open Repository

【 摘 要 】

Estrogen receptor, overexpressed in 70% breast cancer, is a potential interest for several disease indications (e.g. breast cancer, metabolic diseases, or osteoporosis) and an important therapeutic target in the clinical treatment of breast cancers. In order to synthesize the potential down-regulator of estrogen receptor, derivatives of diosgenin glycosides (abbreviated as DG) were designed by conjugation of diosgenin and disaccharide structure (α-L-rhamnopyranosyl-(1→2)-α-L-arabinopyranose) from β-hederin. Each of thirteen DG compounds (00 to 12) bears an exclusive structure according to the glycosylated sugar groups on disaccharide structure. As a result, DG series compounds showed great differences in cytotoxicity and ER inhibition effect. Among the six cytotoxic DG compounds, DG03 showed the most potential activity as an ER down-regulator and inhibited cell growth by inducing apoptosis. Experimental data showed that DG03 specifically suppressed the protein and mRNA expression of ERα in MCF-7 cells. ER-ERE (estrogen responsive element) binding activity was tested by electrophoretic mobility shift assay (EMSA), and both classical and non-classical DNA binding activities were decreased by treatment of DG03. Therefore, ER-mediated gene expression, such as c-Myc, cyclinD1 and pS2 were also reduced, indicating the possibility of cell cycle arrest and inactivation ER signaling. Further research also demonstrated that DG03 reduced phosphorylation of tyrosine kinase Src and inhibited signal transduction through phosphoinositide 3-kinase (PI3K/AKT) and MAPK pathways. In order to examine the apoptotic effect, three kinds of breast cell lines, such as non-tumorigenic epithelial MCF-10A, ERα-positive MCF-7 and ERα-negative MDA-MB-231 cells were adopted to test apoptotic effect by using fluorescence-activated cell sorting (FACS). As a result, MCF-7 cells showed the most significant apoptosis compared with other two cell lines, indicating that DG03 selectively induced apoptosis in ER-positive MCF-7 breast adenocarcinoma. Overall, ER-targeted semi-synthesized DG03 showed great effectiveness as an ER down-regulator and a potential anti-cancer candidate in the treatment of ER-positive breast cancers.