title: The induction of apoptosis by a newly synthesized diosgenyl saponin through the suppression of estrogen receptor-α in MCF-7 human breast cancer cells.
abstract: Estrogen receptor (ER)-α is an important therapeutic target in the clinical treatment of breast cancer. A potential down-regulator of ER-α, diosgenyl α-L-rhamnopyranosyl-(1→2)-[β-D-xylopyranosyl-(1→4)]-α-L-arabinopyranoside is a newly synthesized diosgenyl saponin named compound 22. This study evaluated the in vitro mechanism of compound 22 as an anticancer agent for breast cancer. Our results indicated that compound 22 selectively inhibited proliferation and induced apoptosis in ER-positive MCF-7 cells, compared with ER-negative MDA-MB-231 and MCF-10A cells. Western blot analysis showed that compound 22 decreased the expression of procaspase-3, procaspase-8, and survivin; and increased the expression of Fas ligand and cleaved PARP1 in MCF-7 cells, indicating that compound 22-induced apoptosis was mediated by the extrinsic pathway. This apoptosis was associated with the suppression of ER-α protein and mRNA expression and the inhibition of ER-DNA binding to the estrogen responsive element. Moreover, ER-α mediated gene expression such as c-Myc and cyclin D1 was reduced, and the activation of p38 and ERK 1/2 was significantly decreased after treatment with compound 22 in MCF-7 cells. Taken together, these results demonstrate that compound 22 down-regulates ER-α expression and induces apoptosis through the extrinsic pathway, suggesting that compound 22 may be effective in the treatment of ER-positive breast cancer.
authors.affiliation: Natural Products Research Institute, College of Pharmacy, Seoul National University, 1 Gwanak-ro, Gwanak-gu, Seoul, 151-742, Republic of Korea.
authors.forename: Jaemoo
authors.initials: J
authors.lastname: Chun
authors.forename: Lina
authors.initials: L
authors.lastname: Han
authors.forename: Mei Ying
authors.initials: MY
authors.lastname: Xu
authors.forename: Bo
authors.initials: B
authors.lastname: Wang
authors.forename: Mao Sheng
authors.initials: MS
authors.lastname: Cheng
authors.forename: Yeong Shik
authors.initials: YS
authors.lastname: Kim
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D018929:Cell Culture Techniques; D002470:Cell Survival / Q000187:drug effects; D053938:DNA Fragmentation / Q000187:drug effects*; D004144:Diosgenin / Q000138:chemical synthesis* / Q000494:pharmacology; D024202:Electrophoretic Mobility Shift Assay; D047628:Estrogen Receptor alpha / Q000037:antagonists & inhibitors*; D006801:Humans; D061986:MCF-7 Cells; D015394:Molecular Structure; D012503:Saponins / Q000138:chemical synthesis* / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; C506487:ESR1 protein, human; D047628:Estrogen Receptor alpha; D012503:Saponins; C000599089:diosgenyl rhamnopyranosyl-(1-2)-(xylopyranosyl-(1-4))arabinopyranoside; D004144:Diosgenin