quercetin and Breast-Neoplasms

During the last decade it has been found that chalcones and quinazolines are promising inhibitors of ABCG2. The combination of these two scaffolds offers a new class of heterocyclic compounds with potentially high inhibitory activity against ABCG2. For this purpose we investigated 22 different heterodimeric derivatives. In this series only methoxy groups were used as substituents as these had been proven superior for inhibitory activity of chalcones. All compounds were tested for their inhibitory activity, specificity and cytotoxicity. The most potent ABCG2 inhibitor in this series showed an IC50 value of 0.19 μM. It possesses low cytotoxicity (GI50 = 93 μM), the ability to reverse MDR and is nearly selective toward ABCG2. Most compounds containing dimethoxy groups showed slight activity against ABCB1 too. Among these three compounds (17, 19 and 24) showed even higher activity toward ABCB1 than ABCG2. All inhibitors were further screened for their effect on basal ATPase activity. Although the basal ATPase activity was partially stimulated, the compounds were not transported by ABCG2. Thus, quinazoline-chalcones are a new class of effective ABCG2 inhibitors.

Topics: ATP Binding Cassette Transporter, Subfamily G, Member 2; Breast Neoplasms; Chalcones; Cytotoxins; Female; Humans; Neoplasm Proteins; Quinazolines; Structure-Activity Relationship; Tumor Cells, Cultured

Aromatase, a cytochrome P450 enzyme complex present in breast tissues, plays a significant role in the biosynthesis of important endogenous estrogens from androgens. The source of estrogen production in breast cancer tissues is intra-tumoral aromatase, and inhibition of aromatase may inhibit the growth stimulation effect of estrogens in breast cancer tissues. Consequently, aromatase is considered a useful therapeutic target in the treatment and prevention of estrogen-dependent breast cancer. Recently, different natural products and synthetic compounds have been rapidly developed, studied, and evaluated for aromatase inhibitory activity. Aromatase inhibitors are classified into two categories on the basis of their chemical structures, i.e., steroidal and nonsteroidal aromatase inhibitors. This review highlights the synthetic steroidal and nonsteroidal aromatase inhibitors reported in the literature in the last few years and will aid medicinal chemists in the design and synthesis of novel and pharmacologically-potent aromatase inhibitors for the treatment of breast cancer.

Topics: Antineoplastic Agents; Aromatase; Aromatase Inhibitors; Breast Neoplasms; Drug Design; Estrogens; Female; Humans; Molecular Conformation; Structure-Activity Relationship

In the course of our ongoing efforts to develop novel quercetin conjugates with enhanced stability profiles, we introduced an isopropyloxycarbonylmethoxy (POC) group to 7-OH and/or 3-OH of quercetin and prepared three novel quercetin conjugates. The quercetin-POC conjugates were stable up to 96 h in PBS but slowly hydrolyzed with half-lives of 1-54 h in cell-free culture medium, which is reminiscent of the stability profiles of the previously reported quercetin-POM (pivaloxymethyl) conjugates. However, the quercetin-POC conjugates were more susceptible to passive transport, intracellular hydrolysis, and metabolism in breast cancer (MCF-7) cell line compared with their POM congeners to result in low concentration of quercetin in this cell line and thereby low antiproliferative effect. In contrast, upon incubation with colorectal carcinoma HCT116 cells, the quercetin-POC conjugates were shown to undergo slow hydrolysis and metabolism to maintain concentrations of the active quercetin species high enough to exert enhanced cytotoxicity. Taken together, the quercetin-POC conjugates synthesized in this study exhibited cell type-specific stability as well as bioactivity profiles, which warrants further investigation into the underlying mechanisms and therapeutic potential.

Topics: Antineoplastic Agents; Breast Neoplasms; Cell Line, Tumor; Cell Proliferation; Colorectal Neoplasms; Drug Stability; Female; Humans; Hydrolysis; Quercetin; Solubility

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

To produce rhamnetin using enzymatic engineering, poplar O-methyltransferase-7 and its mutants were prepared based on the rational enzyme design, and the production of rhamnetin was compared with the results obtained using the wild type enzyme. In addition, the potential of using rhamnetin as a cancer chemopreventive agent was compared with that of quercetin in MDA-MB-231 human breast cancer cells, and their bioavailabilities were tested in Dulbecco's modified Eagle's medium.

Topics: Antineoplastic Agents; Breast Neoplasms; Cell Line, Tumor; Drug Design; Female; Humans; Methyltransferases; Molecular Structure; Mutation; Populus; Protein Engineering; Quercetin

The present study utilizes for the first time the structural information of aromatase, an important pharmacological target in anti-breast cancer therapy, to extract the pharmacophoric features important for interactions between the enzyme and its substrate, androstenedione. A ligand-based pharmacophore model developed from the most comprehensive list of nonsteroidal aromatase inhibitors (AIs) is described and explained, as well. This study demonstrates that the ligand-based pharmacophore model contributes to efficacy while the structure-based model contributes to specificity. It is also shown that a 'merged' model (i.e., a merged structure-based and ligand-based model) can successfully identify known AIs and differentiate between active and inactive inhibitors. Therefore, this model can be effectively used to identify the next generation of highly specific and less toxic aromatase inhibitors for breast cancer treatment.

Topics: Antineoplastic Agents; Aromatase; Aromatase Inhibitors; Binding Sites; Breast Neoplasms; Computer Simulation; Drug Design; Female; Humans; Models, Chemical; Models, Molecular; Structure-Activity Relationship

This study investigated the effect of naturally occurring flavonoids and synthetic aurone derivatives on the formation of cardiotoxic doxorubicinol and transport of doxorubicin in breast cancer cells. Quercetin significantly inhibited the formation of doxorubicinol. Quercetin and aurones did not significantly affect transport of [14C]doxorubicin in human resistant breast cancer cells. In conclusion, quercetin should be further tested for its potency to decrease doxorubicin-mediated toxicity.

Topics: Antibiotics, Antineoplastic; Benzofurans; Biological Transport; Breast Neoplasms; Cell Line, Tumor; Doxorubicin; Female; Flavonoids; Humans; Metabolism; Quercetin

A series of polyhydroxylated 2-phenylbenzothiazoles 3 has been prepared by demethylation of the precursor methoxylated 2-phenylbenzothiazoles 9. The key step in the construction of the benzothiazole nucleus involves a Jacobson cyclization of methoxylated thiobenzanilides 8. The target compounds inhibit WiDr human colon tumor cells and MCF-7 human mammary tumor cells in vitro with IC50 values in the low micromolar range, but the activity against MCF-7 cells is not related to estrogen receptor-binding affinity. None of the compounds showed selective cytotoxicity against Abelson virus-transformed ANN-1 cells encoded with the pp120gag-abl tyrosine kinase compared with the parental 3T3 line. Compounds were only marginally inhibitory to the EGF receptor-associated protein tyrosine kinase from a membrane preparation of A431 cells. The most active compound was 4,6-dihydroxy-2-(4-hydroxyphenyl)benzothiazole (3b) which has the same overall hydroxyl substitution pattern as genistein (1a). The compounds were weakly cytotoxic for an EGF receptor, overexpressing cell line HN5, but when tested for differential toxicity against the EGF receptor tyrosine kinase or the PDGF receptor tyrosine kinase in a standard mitogenesis assay utilizing human fibroblasts, no discrimination was observed. In this assay, the compounds inhibited DNA synthesis when added to cells during S phase. This suggests that inhibition could not be interpreted in terms of tyrosine kinase inactivation but more likely as a relatively broad specificity for the ATP-binding domain of other kinases such as thymidine kinase.

Topics: 3T3 Cells; Animals; Antineoplastic Agents; Breast Neoplasms; Cell Division; Colonic Neoplasms; ErbB Receptors; Fibroblasts; Genistein; Humans; Hydroxylation; Isoflavones; Mice; Molecular Structure; Protein-Tyrosine Kinases; Quercetin; Structure-Activity Relationship; Thiazoles; Tumor Cells, Cultured