chrysin and Breast-Neoplasms

Chrysin, a natural compound isolated from various plants, such as the blue passion flower (

Topics: Breast Neoplasms; DNA; DNA Breaks, Double-Stranded; DNA End-Joining Repair; DNA Repair; Female; Flavonoids; Genomic Instability; Humans

Breast cancer is one of the most significant causes of female cancer death worldwide. To explore the possibility of a novel chemo-preventive strategy for improving breast cancer treatment, the anticancer effects of two natural compounds, Artemisinin (Art) and Chrysin (Chr), against T47D breast cancer cells were investigated.. For this purpose, Art and Chr were co-encapsulated in PEGylated PLGA nanoparticles (NPs) and the synthesized NPs were characterized by FE-SEM, FTIR, and DLS and then, MTT assay was used to assess and compare the cytotoxicity of various concentrations of the chemotheruptic molecules in pure and nanoformulated forms as well as in alone and combination state after 48 h exposure time. Drug release study was performed using the dialysis method. Also, the mRNA levels of hTERT genes expression were studied by quantitative real-time PCR.. The results showed that pure and formulations drugs exhibited dose-dependent cytotoxicity against T47D cells and especially, Art/Chr-PLGA/PEG NPs had a more synergistic anti-proliferative effect and significantly arrested the growth of cancer cells than the other groups. Moreover, Real-time PCR results revealed that Art, Chr and combination of Art-Chr in pure and encapsulated forms inhibited hTERT gene expression.. It was found that Art/Chr-PLGA/PEG NPs relative to pure combination could further decline hTERT expression in all concentrations. Our study demonstrated that Art/Chr-PLGA/PEG NPs based combinational therapy holds promising potential for the treatment of breast cancer.

Topics: Artemisinins; Breast Neoplasms; Cell Line; Female; Flavonoids; Gene Expression; Humans; Polyethylene Glycols

Metformin (MET) is a well-known anti-diabetic drug that also has anti-cancer effects. However, high therapeutic doses of MET on cancer cells and the low efficacy of combinatory therapeutic approaches limit its clinical application. Recent studies have shown that chrysin (CHR) can improve the pharmaceutical efficacy of MET by suppressing human telomerase reverse transcriptase (hTERT) and cyclin D1 gene expression.. This study aimed to develop different ratios of methoxy poly(ethylene glycol)-b-poly(e-caprolactone) (MPEG-PCL) micelles for breast cancer to co-deliver a synergistic CHR/MET combination.. CHR/MET drug-loaded micelles were prepared by modified thin-film hydration.Fourier infrared spectrum, gel permeation chromatography, transmission electron microscopy, and high-performance liquid chromatography were used to evaluate the physicochemical properties of nanostructures. Cell proliferation and cell apoptosis were assessed by MTT and Annexin V-FITC/PI double staining method. The gene expression of hTERT and cyclin D1 was measured by real-time PCR assay. A subcutaneous mouse T47D xenograft model was established to evaluate the in vivo efficiency.. When the ratio of MPEG-PCL was 1:1.7, the highest drug loading rate and encapsulation efficiency of CHR (11.31±0.37) and MET (12.22±0.44) were observed. Uniform MPEG-PCL micelles of 51.70±1.91 nm allowed MET to incorporate with CHR, which were co-delivered to breast cancer cells. We demonstrated that CHR/MET co-delivery micelles showed a good synergistic effect on inhibiting proliferation in T47D cells (combination index=0.87) by suppressing hTERT and cyclin D1 gene expression. Compared to the free CHR/MET group, the apoptosis rate on T47D cells by CHR/MET nano-micelles significantly improved from 71.33% to 79.25%. The tumour volume and tumour weight of the CHR/MET group increased more slowly than that of the single-drug treatment group (P<0.05). Compared to the CHR/MET group, the tumour volume and tumour weight of the CHR/MET nano-micelle group decreased by 42% and 59%, respectively.. We demonstrated that ratiometric CHR/MET micelles could provide an effective technique for the treatment of breast cancer.

Topics: Animals; Antineoplastic Agents; Apoptosis; Breast Neoplasms; Cell Proliferation; Cell Survival; Dose-Response Relationship, Drug; Drug Carriers; Drug Screening Assays, Antitumor; Female; Flavonoids; Mammary Neoplasms, Experimental; Metformin; Mice; Mice, Nude; Micelles; Molecular Structure; Nanoparticles; Polyesters; Polyethylene Glycols; Structure-Activity Relationship

Cancer, which is defined as abnormal cell growth, is one of the biggest public health problems in the world. Natural compounds, such as polyphenols, are used as chemo- preventive and chemotherapeutic agents in different types of cancer owing to their antioxidant, antineoplastic, and cytotoxic properties. To improve their bioavailability and releasing behavior, hydrogel systems with high drug loadingg, stability and hydrophilic nature have been designed.. We conducted the present study to investigate the anticancer effects of curcumin and chrysin loaded in the alginate-chitosan hydrogel on breast cancer (T47D) and lung cancer (A549).. The curcumin-chrysin-loaded alginate-chitosan hydrogels were prepared through the ionic gelation mechanism utilizing CaCl2. The prepared hydrogels were studied by using the Fourier Transform Infrared Spectroscopy (FTIR) and Scanning Electron Microscopy (SEM). The MTT and DAPI staining assays were employed for cytotoxicity and apoptosis studies of curcumin-chrysin- loaded alginate-chitosan hydrogels. The effects of the curcumin-chrysin-loaded alginate-chitosan hydrogels on the cell cycle of cell lines T47D and A549 were also evaluated using the propidium iodide staining.. The curcumin-chrysin-loaded alginate-chitosan hydrogels could significantly (p<0.05) reduce the viability and induce apoptosis. Morover G2/M causes arrest of the cell cycle in both A549 and T47D cell lines.. The alginate-chitosan hydrogels could work best as an enhanced anticancer drug delivery system.

Topics: Alginates; Antineoplastic Agents; Breast Neoplasms; Cell Line; Chitosan; Curcumin; Drug Carriers; Female; Flavonoids; Humans; Hydrogels; Lung

Chrysin (CHR), a flavone found in multiple vegetables, fruits and mushrooms has been explored so far as a neurotropic, anti-inflammatory and anti-cancer biomolecule. Despite the stated therapeutic potential, low solubility and bioavailability limit its therapeutic benefit. To circumvent these drawbacks, development of chrysin liposomes (CLPs) is reported in the present investigation. The CLPs were developed by electrostatic deposition assisted film hydration method using chitosan/lecithin to protect chrysin in the nano-lipoidal shell. Developed CLPs were extensively characterized by DSC, XPRD, FE-SEM, TEM, particle size, polydispersity index, zeta potential, percent drug loading and encapsulation efficiency. These CLPs were further characterized by

Topics: Breast Neoplasms; Female; Flavonoids; Humans; Liposomes; Molecular Docking Simulation; Particle Size; Static Electricity

Breast cancer is the most frequent cause of cancer in women. In the current study, transition metal ruthenium was complexed with flavonoid chrysin to evaluate the chemotherapeutic potential of this compound in Michigan Cancer Foundation-7 (MCF-7) human mammary cancer cell line and 7,12-dimethylbenz(α)anthracene-induced mammary cancer in female Sprague-Dawley rats. The characterizations of the complex were accomplished through UV-visible, NMR, IR, Mass spectra, and XRD techniques and antioxidant activity was assessed by DPPH, FRAP, and ABTS methods. In vitro studies included cell viability, cell cycle analysis, DNA fragmentation, and marker analysis by western blot analysis and found that complex treatment suppressed cell growth-induced cell cycle arrest and enhanced the induction of apoptosis in cancer cells. Moreover, complex treatment modulated signaling pathways including mTOR, VEGF, and p53 in the MCF-7 cells. Acute and subacute toxicity was performed in rats to determine the therapeutic doses. Breast cancer in rats was initiated by the administration of 7,12-dimethylbenz(α)anthracene (0.5 mg/100 g body weight) via single tail vein injection. The histopathological analysis after 24 weeks of carcinogenesis study depicted substantial repair of hyperplastic lesions. Immunohistochemical analysis revealed upregulation of Bax and p53 and downregulation of Bcl2 proteins and TUNEL assay showed an increase in apoptotic index in ruthenium-chrysin-treated groups as compared to the carcinogen control. Our findings from the in vitro and in vivo study support the continued investigation of ruthenium-chrysin complex possesses a potential chemotherapeutic activity against breast cancer and was efficient in reducing hyperplastic lesions in the mammary tissues of rats by inducing apoptosis.

Topics: Animals; Apoptosis; bcl-2-Associated X Protein; Breast Neoplasms; Cell Cycle Checkpoints; Cell Line, Tumor; Cell Proliferation; Cell Survival; DNA Fragmentation; Female; Flavonoids; Humans; Male; Mammary Neoplasms, Experimental; MCF-7 Cells; Proto-Oncogene Proteins c-bcl-2; Rats; Rats, Sprague-Dawley; Ruthenium; Tumor Suppressor Protein p53

Chrysin (CH), a phytoconstituent has numerous pharmacological activities including anticancer activity. However, CH suffers from a drawback of poor aqueous solubility and in turn poor bioavailability limiting its clinical utility. In this work CH loaded folate-conjugated pluronic PF127-pluronic F68 mixed micelles were prepared with an objective to augment oral bioavailability and cytotoxicity of CH in human breast cancer cell line MCF-7 by active targeting mechanism. Folate-conjugated PF127 was synthesized and used for preparation of CH-MM. Optimized batch (using factorial design) of CH-MM was characterized by Fourier-transform infrared spectroscopy (FTIR), transmission electron microscopy (TEM), atomic force microscopy (AFM), in vitro CH release, in vivo study, and in vitro cell line study. FTIR study suggested encapsulation of CH into the micelle core. CH-MM showed controlled release of CH releasing higher amount (2.5 fold) in 24 h when compared to CH alone (A-CH). Further significant increase in C

Topics: Administration, Oral; Animals; Antineoplastic Agents; Biological Availability; Breast Neoplasms; Delayed-Action Preparations; Drug Carriers; Drug Compounding; Drug Screening Assays, Antitumor; Excipients; Female; Flavonoids; Folic Acid; Humans; MCF-7 Cells; Micelles; Poloxamer; Polyethyleneimine; Rats; Rats, Wistar

In this study, we explored whether co-nanoencapsulated Curcumin (Cur) and Chrysin (Chr), natural herbal compounds with antitumor activities, regulate miR-132 and miR-502c and their downstream targets, leading to the synergistic growth inhibition in MDA-MB-231 breast cancer cells. For this purpose, Cur and Chr were co-encapsulated into PLGA-PEG nanoparticles (NPs) and characterized through DLS, FTIR and FE-SEM. MTT assay and cell cycle arrest analysis revealed that CurChr-loaded NPs had a considerable synergistic cytotoxicity against MDA-MB-231 cells with more cell accumulation in G2/M phase compared to the other groups. In addition, highest percentage of cell apoptosis was acquired in cells treated with CurChr-loaded NPs according to apoptosis analysis. Real-time PCR findings revealed that co-encapsulated form of Cur and Chr than free combination could further upregulate miR-132 and miR-502c expression (

Topics: Antineoplastic Agents, Phytogenic; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Breast Neoplasms; Cell Line, Tumor; Cell Proliferation; Curcumin; Drug Delivery Systems; Drug Liberation; Flavonoids; Gene Expression Regulation, Neoplastic; Humans; MicroRNAs; Nanoparticles; Polyethylene Glycols; Polyglactin 910; Spectroscopy, Fourier Transform Infrared; Up-Regulation

Objective: To explore the possibility of a novel chemopreventive strategy for improving breast cancer treatment,\ the anticancer effects of a combination two natural compounds, Chrysin and Metformin, against T47D breast cancer\ cells were investigated. Materials and Methods: After treatment of T47D cells with Metformin, Chrysin and the two\ drugs in combination, toxicity to cancer cells was evaluated by MTT assay. Real time PCR was then used to determine\ the expression levels of hTERT and cyclin D1 genes. Results: The MTT test findings showed that the combination of\ metformin and chrysin had high synergistic effects in killing cancer cells. In addition PCR demonstrated a significant\ decrease in cyclin D1 and hTERT gene expression in the T47D breast cancer cell line. Conclusion: The conmbination\ of metformin and chrysin suppressing hTERT and cyclin D1 gene expression might offer an appropriate approach for\ breast cancer therapy.

Topics: Apoptosis; Breast Neoplasms; Cell Proliferation; Cyclin D1; Drug Combinations; Drug Synergism; Female; Flavonoids; Gene Expression Regulation, Neoplastic; Humans; Hypoglycemic Agents; Metformin; Telomerase; Tumor Cells, Cultured

Topics: Animals; Antineoplastic Agents; Breast Neoplasms; Cell Line, Tumor; Cell Proliferation; Drug Carriers; Female; Flavonoids; Humans; Lactic Acid; Mammary Neoplasms, Experimental; Matrix Metalloproteinase 2; Matrix Metalloproteinase 9; Mice; Nanoparticles; Phosphatidylinositol 3-Kinases; Polyglycolic Acid; Polylactic Acid-Polyglycolic Acid Copolymer; Tissue Inhibitor of Metalloproteinase-1; Tissue Inhibitor of Metalloproteinase-2

The development of nanotherapy has presented a new method of drug delivery targeted directly to the neoplasmic tissues, to maximize the action with fewer dose requirements. In the past two decades, poly(lactic-co-glycolic acid) (PLGA) has frequently been investigated by many researchers and is a popular polymeric candidate, due to its biocompatibility and biodegradability, exhibition of a wide range of erosion times, tunable mechanical properties, and most notably, because it is a FDA-approved polymer. Chrysin is a natural flavonoid which has been reported to have some significant biological effects on the processes of chemical defense, nitrogen fixation, inflammation, and oxidation. However, the low solubility in water decreases its bioavailability and consequently disrupts the biomedical benefits. Being loaded with PLGA-PEG increases chrysin solubility and drug tolerance, and decreases the discordant effects of the drug. The well-structured chrysin efficiently accumulates in the breast cancer cell line (T47D). In the present study, the structure and chrysin loading were delineated using proton nuclear magnetic resonance (HNMR), Fourier-transform infrared spectroscopy (FT-IR), and scanning electron microscopy (SEM), and the in vitro cytotoxicity of pure and nanochrysin was studied by the MTT assay. Next, the RNA was exploited and the cytotoxic effects of chrysin were studied by real-time PCR. In conclusion, the nanochrysin therapy developed is a novel method that could increase cytotoxicity to cancer cells without damaging the normal cells, and would be promising in breast cancer therapy.

Topics: Breast Neoplasms; Cytotoxins; Drug Carriers; Female; Flavonoids; Humans; Lactic Acid; MCF-7 Cells; Nanoparticles; Polyethylene Glycols; Polyglycolic Acid; Polylactic Acid-Polyglycolic Acid Copolymer

The composition of Morinda citrifolia (M. citrifolia) was determined using high-performance liquid chromatography (HPLC), and the anticancer effects of M. citrifolia extract evaluated in HepG2, Huh7, and MDA-MB-231 cancer cells. M. citrifolia fruit extracts were obtained by using five different organic solvents, including hexane (Hex), methanol (MeOH), ethyl acetate (EtOAc), chloroform (CHCl3), and ethanol (EtOH). The water-EtOAc extracts from M. citrifolia fruits was found to have the highest anticancer activity. HPLC data revealed the predominance of chrysin in water-EtOAc extracts of M. citrifolia fruit. Furthermore, the combined effects of cotreatment with apigenin and chrysin on liver and breast cancer were investigated. Treatment with apigenin plus chrysin for 72-96 h reduced HepG2 and MDA-MB-231 cell viability and induced apoptosis through down-regulation of S-phase kinase-associated protein-2 (Skp2) and low-density lipoprotein receptor-related protein 6 (LRP6) expression. However, the combination treatment for 36 h synergistically decreased MDA-MB-231 cell motility but not cell viability through down-regulation of MMP2, MMP9, fibronectin, and snail in MDA-MB-231 cells. Additionally, chrysin combined with apigenin also suppressed tumor growth in human MDA-MB-231 breast cancer cells xenograft through down-regulation of ki-67 and Skp2 protein. The experimental results showed that chrysin combined with apigenin can reduce HepG2 and MDA-MB-231 proliferation and cell motility and induce apoptosis. It also offers opportunities for exploring new drug targets, and further investigations are underway in this regard.

Topics: Animals; Apigenin; Apoptosis; Breast Neoplasms; Cell Line, Tumor; Cell Movement; Cell Proliferation; Drug Synergism; Female; Flavonoids; Fruit; Humans; Liver Neoplasms; Low Density Lipoprotein Receptor-Related Protein-6; Matrix Metalloproteinase 2; Mice; Mice, Inbred BALB C; Mice, Nude; Morinda; Plant Extracts; S-Phase Kinase-Associated Proteins

Nano-therapy exhibit the potential of revolutionizing cancer therapy. This field introduces nanovectors/nanocarriers for anticancer drugs targeted delivery, and also finds application in imaging. Chrysin, a natural flavonoid, was recently studied as having important biological roles in chemical defenses, nitrogen fixation, anti-inflammatory, and anti-oxidant properties. We aim at studying the effect of nano-chrysin on breast cancer cell line.. The effect of chrysin loaded PCL-PEG-PCL was studied on T47D breast cancer cell line. The structure and drug-loading of chrysin were characterized using. Data analysis from MTT assay showed that chrysin has a time-dependent cytotoxic effect on T47D cell line. Furthermore, the results of Real-time PCR suggested that encapsulated chrysin have higher antitumor effect on gene expression of FTO, BRCA1 and hTERT than free chrysin.. Combined nano-chrysin therapy will not only improve cancer cell cytotoxicity, but also be a complementary and potential complex in breast cancer therapy.

Topics: Antineoplastic Agents; Breast Neoplasms; Cell Line, Tumor; Cell Survival; Dose-Response Relationship, Drug; Drug Carriers; Female; Flavonoids; Humans; Nanoparticles; Polyesters; Polyethylene Glycols

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

Polymeric nanoparticles are attractive materials that have been widely used in medicine for drug delivery, with therapeutic applications. In our study, polymeric nanoparticles and the anticancer drug, chrysin, were encapsulated into poly (D, L-lactic-co-glycolic acid) poly (ethylene glycol) (PLGA-PEG) nanoparticles for local treatment.. PLGA: PEG triblock copolymers were synthesized by ring-opening polymerization of D, L-lactide and glycolide as an initiator. The bulk properties of these copolymers were characterized using 1H nuclear magnetic resonance spectroscopy and Fourier transform infrared spectroscopy. In addition, the resulting particles were characterized by scanning electron microscopy.. The chrysin encapsulation efficiency achieved for polymeric nanoparticles was 70% control of release kinetics. The cytotoxicity of different concentration of pure chrysin and chrysin loaded in PLGA-PEG (5-640μM) on T47-D breast cancer cell line was analyzed by MTT-assay.. There is potential for use of these nanoparticles for biomedical applications. Future work should include in vivo investigation of the targeting capability and effectiveness of these nanoparticles in the treatment of breast cancer.

Topics: Apoptosis; Blotting, Western; Breast Neoplasms; Cell Cycle; Cell Proliferation; Cyclin D1; Drug Carriers; Drug Delivery Systems; Female; Flavonoids; Humans; Lactic Acid; Nanoparticles; Polyethylene Glycols; Polyglycolic Acid; Polylactic Acid-Polyglycolic Acid Copolymer; Real-Time Polymerase Chain Reaction; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Tumor Cells, Cultured

Tumor hypoxia commonly occurs in solid tumors, and correlates with metastasis. Current cancer therapies are inefficient in curing metastatic disease. Herein, we examined effect of Thai propolis extract and its major constituent, chrysin, on hypoxic survival of 4T1 mouse breast cancer cells in vitro, and investigated its underlying mechanism. In vivo effect of chrysin on metastatic progression of cancer cells was studied, both as a single agent and in combination with another antimetastatic agent, agonistic monoclonal antibody targeting the DR5 TRAIL receptor (DR5 mAb). Thai propolis extract and chrysin decreased survival of 4T1 cells after exposure to hypoxia (1% O2), for 2 days. Immunoblot analysis revealed that chrysin inhibited hypoxia-induced STAT3 phosphorylation without affecting HIF-1α protein level. Chrysin also abrogated hypoxia-induced VEGF gene expression as determined by qRT-PCR. The in vivo effect of chrysin was determined in a spontaneous metastasis mouse model of breast cancer, either alone or in combination with DR5 mAb. Daily oral administration of chrysin in Balb/c mice implanted with 4T1 cells significantly suppressed growth of lung metastatic colonies. Moreover, antimetastatic activity of DR5 mAb was enhanced when given in combination with chrysin. We demonstrate that chrysin has potential in controlling metastatic progression.

Topics: Animals; Breast Neoplasms; Cell Hypoxia; Cell Line, Tumor; Cell Proliferation; Cell Survival; Female; Flavonoids; Gene Expression Regulation, Neoplastic; Humans; Mice; Neoplasm Metastasis; Receptors, TNF-Related Apoptosis-Inducing Ligand; STAT3 Transcription Factor

Chinese propolis (CP) is a natural product collected by honeybees and a health food raw material. Previous studies have shown that CP exhibits a broad spectrum of biological activities including anticancer, antioxidant, antibacterial, anti-inflammatory, and antiviral activities. The focuses of the present study were the standardization of CP and the possible mechanisms of its active anticancer ingredients. Nine samples of CP were collected from different locations in China. Analyses of the CP samples revealed that all 9 had similar chemical compositions. Parameters analyzed included the CP extract dry weight, total phenolic content, and DPPH free radical scavenging activities. The active anticancer ingredient was isolated, characterized against human MDA-MB-231 breast cancer cells, and identified as chyrsin, a known potent anticancer compound. Chrysin is present at high levels in all 9 of the CP samples, constituting approximately 2.52% to 6.38% of the CP extracts. However, caffeic acid phenethyl ester (CAPE), another potent active ingredient is present in low levels in 9 samples of CP, constituting approximately 0.08% to 1.71% of the CP extracts. Results from analyses of enzymatic activity indicated that chrysin is a histone deacetylase inhibitor (HDACi) and that it markedly inhibited HDAC8 enzymatic activity (EC(50) = 40.2 μM). In vitro analyses demonstrated that chrysin significantly suppressed cell growth and induced differentiation in MDA-MB-231 cells. In a xenograft animal model (MDA-MB-231 cells), orally administered chrysin (90 mg/kg/day) significantly inhibited tumor growth. Despite the geographical diversity of the 9 samples' botanical origins, their chemical compositions and several analyzed parameters were similar, suggesting that CP is standardized, with chrysin being the major active ingredient. Overall, in vitro and in vivo data indicated that chrysin is an HDAC8 inhibitor, which can significantly inhibit tumor growth. Data also suggested that chrysin might represent a suitable candidate for standardization of CP.

Topics: Animals; Antineoplastic Agents; Breast Neoplasms; Cell Line, Tumor; China; Enzyme Inhibitors; Female; Flavonoids; Histone Deacetylases; Humans; Mice; Mice, Inbred BALB C; Mice, Nude; Propolis; Repressor Proteins; Xenograft Model Antitumor Assays

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

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

A screening of Greek Fabaceae extracts identified the methanolic extract of Podocytisus caramanicus Boiss. & Heldr. as having proliferative activity on human breast cancer cells (MCF-7). Using transient transfection experiments, we have first used three compounds described for their estrogen-like properties, E (2), genistein (Gen) and biochanin A (Bch), as controls to evaluate our cellular model. Secondly, we have demonstrated that the 7- O-beta- D-glucopyranosylchrysin (Glc-chr), the most abundant flavone of the extract, and its aglycone chrysin were able to increase estrogen receptor alpha transcriptional activity in MCF-7 cells. We have also shown that the estrogenic activity of Glc-chr could be completely suppressed by the pure estrogen antagonist ICI 182,780 suggesting that the effect of Glc-chr is mediated by ERalpha.

Topics: Antineoplastic Agents, Phytogenic; Breast Neoplasms; Cell Line, Tumor; Estrogen Receptor alpha; Fabaceae; Flavonoids; Glucosides; Humans; Molecular Structure; Transcription, Genetic

The aryl hydrocarbon receptor (AhR) binds with high affinity to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and related halogenated aromatics, but also binds with lower affinity to structurally diverse exogenous and endogenous chemicals. One study reported that 3-methylcholanthrene (3MC) activated the estrogen receptor (ER) through the AhR, which acts as co-regulatory protein, whereas a recent report showed that 3MC directly bound and activated ERalpha. This study also shows that the AhR agonists benzo[a]pyrene, 3,3',4,4'-tetrachlorobiphenyl, chrysin, 6-methyl-1,3,8-trichlorodibenzofuran, and 3,3'-diindolylmethane also induce ERalpha-dependent transactivation. Moreover, in chromatin immunoprecipitation assays, these compounds induce binding of AhR and ERalpha to the CYP1A1 and pS2 gene promoters, which is consistent with their activities as both selective AhR modulators (SAhRMs) and selective ER modulators (SERMs).

Topics: Benzo(a)pyrene; Benzofurans; Binding Sites; Breast Neoplasms; Cell Line, Tumor; Cytochrome P-450 CYP1A1; Estrogen Receptor alpha; Flavonoids; Humans; Indoles; Ligands; Methylcholanthrene; Polychlorinated Biphenyls; Polychlorinated Dibenzodioxins; Presenilin-2; Promoter Regions, Genetic; Receptors, Aryl Hydrocarbon; Structure-Activity Relationship

Phytoestrogen effects on estrogen action and tyrosine kinase activity have been proposed to contribute to cancer prevention. To study these mechanisms, a number of phytoestrogens and related compounds were evaluated for their effects on DNA synthesis (estimated by thymidine incorporation analysis) in estrogen-dependent MCF-7 cells in the presence of estradiol (E2), tamoxifen, insulin, or epidermal growth factor. We observed that 1) at 0.01-10 microM, genistein and coumestrol enhanced E2-induced DNA synthesis, as did 10 microM enterolactone. Chrysin at 1.0-10 microM and 10 microM luteolin or apigenin inhibited E2-induced DNA synthesis, as did all compounds at > 10 microM, 2) tamoxifen enhanced genistein-induced DNA synthesis but inhibited DNA synthesis induced by all other compounds, and 3) genistein enhanced insulin- and epidermal growth factor-induced DNA synthesis at 0.1-1.0 and 0.1-10 microM, respectively. At higher concentrations, inhibition was observed. Similar effects were seen with coumestrol. In conclusion, the effects of phytoestrogens in the presence of E2 or growth factors are concentration dependent and variable. At low concentrations, genistein and coumestrol significantly enhanced E2-induced and tyrosine kinase-mediated DNA synthesis; at high concentrations, inhibition was observed. Differing effects were observed with the other compounds. The variable effects of phytoestrogens on DNA synthesis must be considered when their roles in cancer prevention or treatment are evaluated.

Topics: 4-Butyrolactone; Anticarcinogenic Agents; Antineoplastic Agents, Hormonal; Breast Neoplasms; Chamomile; Coumestrol; DNA, Neoplasm; Epidermal Growth Factor; Estradiol; Estrogens, Non-Steroidal; Female; Flavonoids; Genistein; Humans; Insulin; Isoflavones; Lignans; Luteolin; Oils, Volatile; Phytoestrogens; Plant Preparations; Plants, Medicinal; Tamoxifen; Tumor Cells, Cultured