apigetrin and Breast-Neoplasms

Flavonoids are an interesting group of natural products ubiquitously present in human diet. Their consumption has been associated with various and differing beneficial health effects. However, several flavonoids have been reported to inhibit the breast cancer resistance protein (BCRP) encoded by the ABCG2 gene. Thus, the consumption of flavonoids with high inhibitory activity could change pharmacokinetics and drug levels of drugs that are BCRP substrates. In cancer patients receiving chemotherapy an increased intake of such flavonoids could lead to adverse effects. We investigated a structurally diverse set of flavonoids, including derivatives with a rare C-methylated structure that were isolated from plants used in traditional medicine. The flavones retusin and ayanin were found to be highly potent inhibitors of BCRP, showing only slightly less potency than Ko143, the most potent ABCG2 inhibitor known so far. The activity data were analyzed by 2D and 3D QSAR analyses and the results revealed the impact of the different substituents at the various positions of the flavonoid core on activity. Additionally, a lateral 2D QSAR analysis of data collected from the literature was performed aiming to derive more general information about the influence of distinct structural features on the inhibitory potency of flavonoids. The comparative QSAR analyses led to a consistent picture of the effects of the different substituents at various positions of the flavone backbone. The following structural features were found to contribute positively to BCRP inhibition: a hydroxyl group in position 5, double bond between position 2 and 3, and a methoxy group in position 3. The exchange of a 3-methoxy group by an OH-group acting also as a hydrogen bond donor, resulted in decrease in activity underlining the potential role of the hydrogen bond acceptor 3-OCH(3) for the interaction with BCRP.

Topics: Antineoplastic Agents; ATP Binding Cassette Transporter, Subfamily B, Member 1; ATP Binding Cassette Transporter, Subfamily G, Member 2; ATP-Binding Cassette Transporters; Breast Neoplasms; Cell Line, Tumor; Drug Resistance, Neoplasm; Female; Flavonoids; Humans; Hydrogen Bonding; Models, Molecular; Neoplasm Proteins; Quantitative Structure-Activity Relationship

Estrogen signaling is mediated by two estrogen receptors (ERs), ERα and ERβ, which have unique roles in the regulation of breast cancer cell proliferation. ERα induces proliferation in response to estrogen and ERβ inhibits proliferation in breast cancer cells, suggesting that ERβ selective ligands may be beneficial for promoting the anti-proliferative action of ERβ. Subtype selective ligands can be identified using transcriptional assays, but cell lines in which ERα or ERβ are independently expressed are required. Of the available reporter cell lines, none have been generated in breast cancer cells to identify subtype selective ligands. Here we describe the generation of two isogenic breast cancer cell lines, Hs578T-ERαLuc and Hs578T-ERβLuc, with stable integration of an estrogen responsive luciferase reporter gene. Hs578T-ERαLuc and Hs578T-ERβLuc cell lines are highly sensitive to estrogenic chemicals and ER subtype selective ligands, providing a tool to characterize the transcriptional potency and subtype selectivity of estrogenic ligands in the context of breast cancer cells. In addition to measuring reporter activity, ERβ target gene expression and growth inhibitory effects of ERβ selective ligands can be determined as biological endpoints. The finding that activation of ERβ by estrogen or ERβ selective natural phytoestrogens inhibits the growth of Hs578T-ERβ cells implies therapeutic potential for ERβ selective ligands in breast cancer cells that express ERβ.

Topics: Antineoplastic Agents; Apigenin; Breast Neoplasms; Cell Line, Tumor; Doxorubicin; Estrogen Receptor alpha; Estrogen Receptor beta; Female; Flavanones; Gene Expression Regulation, Neoplastic; Genes, Reporter; Humans; Ligands; Luciferases