chrysin and Neoplasms

Chrysin belongs to the group of natural polyphenols. It can be found, among others, in honey, propolis and fruits and has a wide range of biological activities, including the prevention of oxidative stress, inflammation, neurodegeneration and carcinogenesis. Being a part of the human diet, chrysin is considered to be a promising compound to be used in the prevention of many diseases, including cancers, diabetes and neurodegenerative diseases such as Alzheimer's or Parkinson's. Nevertheless, due to the low solubility of chrysin in water and under physiological conditions, its bioavailability is low. For this reason, attempts at its functionalization have been undertaken, aiming to increase its absorption and thus augment its in vivo therapeutic efficacy. The aim of this review is to summarize the most recent research on chrysin, including its sources, metabolism, pro-health effects and the effects of its functionalization on biological activity and pharmacological efficacy, evaluated both in vitro and in vivo.

Topics: Animals; Antineoplastic Agents; Biological Availability; Drug Carriers; Eye Diseases; Flavonoids; Humans; Inflammation; Liver; Neoplasms; Neurodegenerative Diseases; Neuroprotection; Polyphenols; Skin Diseases

Pharmacological profile of phytochemicals has attracted much attention to their use in disease therapy. Since cancer is a major problem for public health with high mortality and morbidity worldwide, experiments have focused on revealing the anti-tumor activity of natural products. Flavonoids comprise a large family of natural products with different categories. Chrysin is a hydroxylated flavonoid belonging to the flavone category. Chrysin has demonstrated great potential in treating different disorders, due to possessing biological and therapeutic activities, such as antioxidant, anti-inflammatory, hepatoprotective, neuroprotective, etc. Over recent years, the anti-tumor activity of chrysin has been investigated, and in the present review, we provide a mechanistic discussion of the inhibitory effect of chrysin on proliferation and invasion of different cancer cells. Molecular pathways, such as Notch1, microRNAs, signal transducer and activator of transcription 3 (STAT3), nuclear factor-kappaB (NF-κB), PI3K/Akt, MAPK, etc., as targets of chrysin are discussed. The efficiency of chrysin in promoting anti-tumor activity of chemotherapeutic agents and suppressing drug resistance is described. Moreover, poor bioavailability, as one of the drawbacks of chrysin, is improved using various nanocarriers, such as micelles, polymeric nanoparticles, etc. This updated review will provide a direction for further studies in evaluating the anti-tumor activity of chrysin.

Topics: Antineoplastic Agents; Antioxidants; Drug Resistance, Neoplasm; Flavonoids; Humans; MicroRNAs; Neoplasms; Receptor, Notch1; Signal Transduction; STAT3 Transcription Factor

Phytoestrogens are class of natural compounds that shares structural similarity with estrogen and has the capacity to alter the fertilization in mammals. Till early 1990s, the natural phytoestrogens as well as their synthetic analogues were explored for their fertility modulating activity. During late 1990s, two findings renewed the interest on phytoestrogens as means to control hormone induced cancer: (i) revelation of overexpression of CYP1B1 in breast & ovarian cancer and (ii) protection offered by alphanapthoflavone (ANF) against hormone induced cancer. The objective of the review is to summarize the CYP1B1 inhibitory activity of phytoestrogens and their synthetic analogues reported till date. This review is an attempt to classify phytoestrogens and their synthetic analogues on their chemical architecture rather than simply by their chemical class (flavones, stilbenes etc.). This provides a broader sense to cluster many chemical classes under a particular chemical architecture/framework. Accordingly, we divided the phytoestrogen into three different classes based on two aryl groups (Ar) separated by linker (X), which may be either cyclic (c) or linear (l). The number in subscript to X denotes number of atoms: (i) Ar-cX

Topics: Animals; Antineoplastic Agents, Phytogenic; Classification; Cluster Analysis; Cytochrome P-450 CYP1B1; Enzyme Inhibitors; Humans; Molecular Mimicry; Neoplasms; Phytoestrogens

Protein kinases have been important targets for antitumor targets due to their key roles in regulating multiple cell signaling pathways. Numerous compounds containing flavonoid scaffold as an indispensable anchor have been found to be potent inhibitors of protein kinases. Some of these flavonoids have been in clinical research as protein kinases inhibitors. Thus, the present review mainly focuses on the structural requirement for anticancer potential of flavone derivatives targeting several key serine/threonine protein kinases. This information may provide an opportunity to scientists of medicinal chemistry to design multi-functional flavone derivatives for the treatment of cancer.

Topics: Animals; Antineoplastic Agents; Flavones; Humans; Neoplasms; Protein Binding; Protein Kinase Inhibitors; Protein Serine-Threonine Kinases

Inhibitors of the ubiquitin-proteasome system (UPS) have been the object of research interests for many years because of their potential as anti-cancer agents. Research in this field is aimed at improving the specificity and safety of known proteasome inhibitors. Unfortunately, in vitro conditions do not reflect the processes taking place in the human body. Recent reports indicate that the components of human plasma affect the course of many signaling pathways, proteasome activity and the effectiveness of synthetic cytostatic drugs. Therefore, it is believed that the key issue is to determine the effects of components of the human diet, including effects of chemically active polyphenols on the ubiquitin-proteasome system activity in both physiological and pathological (cancerous) states. The following article summarizes the current knowledge on the direct and indirect synergistic and antagonistic effects between polyphenolic compounds present in the human diet and the efficiency of protein degradation via the UPS.

Topics: Animals; Diet; Humans; Neoplasms; Phenols; Polyphenols; Proteasome Endopeptidase Complex; Ubiquitin

Chrysin is a natural product of a flavonoid compound. Chemically, chrysin consists of two phenyl rings (A and B) and a heterocyclic ring (C). Biologically, chrysin exerts many different physiological activities. In recent years, with the in-depth development for more active drugs, the synthesis and biological activities of chrysin derivatives have been well studied. Besides, structure-activity relationship of chrysin revealed that the chemical construction meets the critical chemical structural necessities of flavonoids for numerous pharmacological activities. It is generally believed that modified chrysin could be more potent than unmodified chrysin. Different modification in the rings of chrysin could possess various degrees of biological activities. This review aims to summarize the mechanism for the activities of chrysin and its derivatives in different rings. We also explored the relationship between biological function and structure-activity of substituted chrysin derivatives with different functional groups. The influence of chrysin derivatives on the proliferation and apoptosis of cancer cells is also investigated. Development of novel drugs based on the biological functions of chrysin could better improve clinical outcomes of affected population, especially for tumor patients and diabetic patients.

Topics: Animals; Antineoplastic Agents; Apoptosis; Biological Products; Drug Discovery; Flavonoids; Humans; Neoplasms; Structure-Activity Relationship

In this review we report the recent advances in anticancer activity of the family of natural occurring flavonoids, covering the time span of the last five years. The bibliographic data will be grouped, on the basis of biological information, in two great categories: reports in which the extract plants bioactivity is reported and the identification of each flavonoid is present or not, and reports in which the anticancer activity is attributable to purified and identified flavonoids from plants. Wherever possible, the targets and mechanisms of action as well as the structure-activity relationships of the molecules will be reported. Also, in the review it was thoroughly investigated the recent discovery on flavonoids containing the 2-phenyl-4H-chromen-4-one system even if some examples of unusual flavonoids, bearing a non-aromatic B-ring or other ring condensed to the base structure are reported.

Topics: Animals; Antineoplastic Agents, Phytogenic; Benzopyrans; Drug Discovery; Flavonoids; Humans; Neoplasms; Plants; Structure-Activity Relationship

Nowadays there is a folk medicine branch called apitherapy that aims to treat diseases with bee products, including honey. Honey has long been known for its medicinal and health promoting properties. It encloses numerous types of phytochemicals with high phenolic and flavonoid content, which contribute to its antioxidant and anti-inflammatory activities. Varieties and variants of polyphenols in honey showed antiproliferative property against several types of cancer. This review focuses on the latest discoveries about the key role of honey in different stages of carcinogenesis, initiation, proliferation and progression, both in vitro and in vivo, as well as on its adjuvant effect in cancer therapy. Although a possible application of honey and its active compounds as drugs against cancer is still far away from clinical practice, scientific results highlight that they could be used as immune booster for patients undergoing chemotherapy. They showed protective effects against the common exasperating and disabling side effects, mostly mucositis.

Topics: Animals; Anti-Inflammatory Agents; Anticarcinogenic Agents; Antioxidants; Apitherapy; Flavonoids; Honey; Humans; Neoplasms; Phenols

The oxidative pentose phosphate pathway (PPP) contributes to tumour growth, but the precise contribution of 6-phosphogluconate dehydrogenase (6PGD), the third enzyme in this pathway, to tumorigenesis remains unclear. We found that suppression of 6PGD decreased lipogenesis and RNA biosynthesis and elevated ROS levels in cancer cells, attenuating cell proliferation and tumour growth. 6PGD-mediated production of ribulose-5-phosphate (Ru-5-P) inhibits AMPK activation by disrupting the active LKB1 complex, thereby activating acetyl-CoA carboxylase 1 and lipogenesis. Ru-5-P and NADPH are thought to be precursors in RNA biosynthesis and lipogenesis, respectively; thus, our findings provide an additional link between the oxidative PPP and lipogenesis through Ru-5-P-dependent inhibition of LKB1-AMPK signalling. Moreover, we identified and developed 6PGD inhibitors, physcion and its derivative S3, that effectively inhibited 6PGD, cancer cell proliferation and tumour growth in nude mice xenografts without obvious toxicity, suggesting that 6PGD could be an anticancer target.

Topics: AMP-Activated Protein Kinase Kinases; AMP-Activated Protein Kinases; Humans; Lipogenesis; Neoplasms; Oxidative Stress; Pentose Phosphate Pathway; Phosphogluconate Dehydrogenase; Protein Serine-Threonine Kinases; Ribulosephosphates; Signal Transduction

Chrysin, a naturally occurring flavone, abundantly found in numerous plant extracts including propolis and in honey is one of the most widely used herbal medicine in Asian countries. Nowadays, chrysin has become the foremost candidate exhibiting health benefits, owing to its multiple bioactivities such as antioxidant, anti-inflammatory, anti-allergic, anti-diabetic, anti-estrogenic, antibacterial and antitumor activities. Anticancer activity is most promising among the multiple pharmacological effects displayed by chrysin. In vitro and in vivo models have shown that chrysin inhibits cancer growth through induction of apoptosis, alteration of cell cycle and inhibition of angiogenesis, invasion and metastasis without causing any toxicity and undesirable side effects to normal cells. Chrysin displays these effects through selective modulation of multiple cell signaling pathways which are linked to inflammation, survival, growth, angiogenesis, invasion and metastasis of cancer cells. This broad spectrum of antitumor activity in conjunction with low toxicity underscores the translational value of chrysin in cancer therapy. The present review highlights the chemopreventive and therapeutic effects, molecular targets and antineoplastic mechanisms that contribute to the observed anticancer activity of chrysin.

Topics: Animals; Antineoplastic Agents; Drug Screening Assays, Antitumor; Flavonoids; Humans; Neoplasms

Various plant polyphenols have been recognized as redox active molecules. This review discusses some aspects of polyphenols' modes of redox action, corresponding structure-activity relationships and their potential to be applied as adjuvants to conventional cytostatic drugs. Polyphenols' antioxidative capacity has been discussed as the basis for targeting oxidative stress and, consequently, for their chemopreventive and anti-inflammatory activities, which may alleviate side-effects on normal cells arising from oxidative stress caused by cytostatics. Some polyphenols may scavenge various free radicals directly, and some of them are found to suppress free radical production through inhibiting NADPH oxidases and xanthine oxidase. Additionally, polyphenols may increase antioxidative defense in normal cells by increasing the activity of NRF2, transcription factor for many protective proteins. The activation of the NRF2-mediated signaling pathways in cancer cells results in chemoresistance. Luteolin, apigenin and chrysin reduce NRF2 expression and increase the chemosensitivity of cancer cells to cytostatic drugs. Their common 5,7-dihydroxy-4H-chromen-4-one moiety, may represent a starting pharmacophore model for designing novel, non-toxic compounds for overcoming chemoresistance. However, prooxidative activity of some polyphenols (quercetin, EGCG) may also provide a basis for their use as chemotherapeutic adjuvants since they may enhance cytotoxic effects of cytostatics selectively on cancer cells. However, considerable caution is needed in applying polyphenols to anticancer therapy, since their effects greatly depend on the applied dose, the cell type, exposure time and environmental conditions.

Topics: Antineoplastic Agents; Antioxidants; Cytostatic Agents; Drug Resistance, Neoplasm; Flavonoids; Free Radicals; Gene Expression Regulation, Neoplastic; Humans; Luteolin; NADPH Oxidases; Neoplasms; NF-E2-Related Factor 2; Oxidative Stress; Polyphenols; Structure-Activity Relationship; Xanthine Oxidase

In vertebrates, the glucuronidation of small lipophilic agents is catalyzed by the endoplasmic reticulum UDP-glucuronosyltransferases (UGTs). This metabolic pathway leads to the formation of water-soluble metabolites originating from normal dietary processes, cellular catabolism, or exposure to drugs and xenobiotics. This classic detoxification process, which led to the discovery nearly 50 years ago of the cosubstrate UDP-glucuronic acid (19), is now known to be carried out by 15 human UGTs. Characterization of the individual gene products using cDNA expression experiments has led to the identification of over 350 individual compounds that serve as substrates for this superfamily of proteins. This data, coupled with the introduction of sophisticated RNA detection techniques designed to elucidate patterns of gene expression of the UGT superfamily in human liver and extrahepatic tissues of the gastrointestinal tract, has aided in understanding the contribution of glucuronidation toward epithelial first-pass metabolism. In addition, characterization of the UGT1A locus and genetic studies directed at understanding the role of bilirubin glucuronidation and the biochemical basis of the clinical symptoms found in unconjugated hyperbilirubinemia have uncovered the structural gene polymorphisms associated with Crigler-Najjar's and Gilbert's syndrome. The role of the UGTs in metabolism and different disease states in humans is the topic of this review.

Topics: Autoimmunity; Chromosome Mapping; Glucuronides; Glucuronosyltransferase; Humans; Hyperbilirubinemia; Neoplasms; Steroids; Terminology as Topic

Topics: Flavonoids; Humans; Immunologic Factors; Immunotherapy; Myeloid-Derived Suppressor Cells; Neoplasms

Chemotherapeutic metal-based compounds are effective anticancer agents; however, their cytotoxic profile and significant side effects limit their wide application. Natural products, especially flavonoids, are a prominent alternative source of anticancer agents that can be used as ligands for the generation of new bioactive complexes with metal ions of known biochemical and pharmacological activities. Herein, we present the synthesis and detailed structural and physicochemical characterizations of three novel complex assemblies of Ga(iii) with the flavonoid chrysin and the ancillary aromatic chelators 1,10-phenanthroline, 2,2'-bipyridine and imidazole. The complexes constitute the only crystallographically characterized structures having a metal core from the boron group elements and a flavonoid as the ligand. The in vitro biological evaluation of the three complexes in a series of cancer cell lines of different origin established their cytotoxicity and ROS generating potential. In particular, the Ga(iii)-chrysin-imidazole complex displayed the highest anticancer efficacy against all cancer cell lines with IC50 values in the low micromolar range (<1.18 μM), a result worth further investigation.

Topics: Antineoplastic Agents; Cell Proliferation; Flavonoids; Gallium; Humans; Molecular Structure; Neoplasms; Structure-Activity Relationship; Tumor Cells, Cultured

Chrysin is a strong inhibitor of breast cancer resistance protein (BCRP) but it is practically insoluble in water. Effective solubilization of chrysin is critical for its pharmaceutical application as an absorption enhancer via inhibition of BCRP-mediated drug efflux.. This study aimed to develop an effective oral formulation of chrysin to improve its in vivo effect as an absorption enhancer.. Solid dispersions (SDs) of chrysin were prepared with hydrophilic carriers having surface acting properties and a pH modulator. In vitro and in vivo characterizations were performed to select the optimal SDs of chrysin.. SDs with Brij®L4 and aminoclay was most effective in increasing the solubility of chrysin by 13-53 fold at varying drug-carrier ratios. Furthermore, SDs significantly improved the dissolution rate and extent of drug release. SDs (chrysin: Brij®L4: aminoclay=1:3:5) achieved approximately 60% and 83% drug release within 1 h and 8 h, respectively, in aqueous medium, while the dissolution of the untreated chrysin was less than 13%. XRD patterns indicated the amorphous state of chrysin in SDs. The SD formulation was effective in improving the bioavailability of topotecan, a BCRP substrate in rats. Following oral administration of topotecan with the SDs of chrysin, the Cmax and AUC of topotecan was enhanced by approximately 2.6- and 2-fold, respectively, while the untreated chrysin had no effect.. The SD formulation of chrysin with Brij®L4 and aminoclay appeared to be promising in improving the dissolution of chrysin and enhancing its in vivo effect as an absorption enhancer.

Topics: Administration, Oral; Animals; Antineoplastic Combined Chemotherapy Protocols; ATP Binding Cassette Transporter, Subfamily G, Member 2; Biological Availability; Clay; Detergents; Drug Compounding; Drug Evaluation, Preclinical; Flavonoids; HT29 Cells; Humans; Hydrophobic and Hydrophilic Interactions; Intestinal Absorption; Male; Neoplasms; Polidocanol; Rats; Rats, Sprague-Dawley; Solubility; Topotecan; Water

Low molecular weight heparin (LMWH) is a natural sulfated glycosaminoglycan with the affinity to proangiogenic factors, rendering it a promising agent for tumor therapy. Inspired by DOX binding to the helix of DNA, mitochondrial damage KLA peptide derivative (mKLA) and anti-angiogenic LMWH-chrysin conjugate (LC) are constructed to simulate the double strands for doxorubicin (DOX) binding (LKD nanocomplex). Initiated and "locked" by DOX, mKLA and LC temporarily aggregate by π-π stacks, electrostatic and hydrophobic interactions in aqueous condition with self-amplified DOX loading (19.07 ± 1.08 wt%). During endosome-lysosome trafficking, DOX protonated by H

Topics: Angiogenesis Inhibitors; Animals; DNA; Doxorubicin; Flavonoids; Hep G2 Cells; Heparin, Low-Molecular-Weight; Hepatocytes; Humans; Intercellular Signaling Peptides and Proteins; Mice, Nude; Mitochondria; Nanoconjugates; Neoplasms; Peptides; Xenograft Model Antitumor Assays

This study is a report about the synthesis iron oxide magnetic nanoparticles (IONPs) which modified with positive and negative charged amino acids (AAs). l-Arginine (Arg) and l-aspartic acid (Asp) which have of guanidinium and carboxylic acid groups, respectively, were selected for this study. After loading chrysin in amino acids modified iron oxide magnetic nanoparticles (F@AAs@Chrysin NPs), it was characterized by XRD, TGA, FTIR, VSM, and TEM techniques. Finally, MTT assays on HFF-2 and HEK-293 cell lines were performed for determination of biocompatibility of AA coated IONPs. The results show that, the ζ-potential and average size of F@Arg@chrysin NPs and F@Asp@chrysin NPs were to -3.87, -2.12 mV, 18.75 ± 2.40 (mean ± SD (

Topics: Amino Acids; Cell Survival; Contrast Media; Drug Carriers; Drug Delivery Systems; Flavonoids; HEK293 Cells; Hemolysis; Humans; Magnetic Resonance Imaging; Magnetite Nanoparticles; Neoplasms

A series of 5,7-disubstituted chrysin, 7-monosubstituted chrysin, 5-monosubstituted chrysin derivatives were synthesized by alkylation, acetylation, benzoylation, carboxymethylation, and evaluated on their antitumor activity of H22 cells in the search for potential antitumor agents. Among them, compound 3 (5,7-diacetyl chrysin) displayed the most potent antitumor activity with IC50 value of 141 μM. Moreover, there is significant up-regulation of G2 in cell cycle of H22.

Topics: Acetylation; Alkylation; Antineoplastic Agents; Cell Division; Cell Line, Tumor; Drug Screening Assays, Antitumor; Flavonoids; G2 Phase; Humans; Neoplasms

Cisplatin-induced nephrotoxicity is the main cause for its dose-limited use in the treatment of various cancers and results in acute renal cell injury through generation of reactive oxygen species. Chrysin possess antioxidant, anti-inflammatory and anti-cancer properties. The aim of this study was to investigate the protective efficacy of chrysin against cisplatin-induced nephrotoxicity.. Thirty male Wistar rats were divided into five groups with six rats in each group. Group I served as control and received corn oil (vehicle of chrysin) for 14 days and 0.9% saline (vehicle of cisplatin) on day 14 only. Group II received a single intraperitoneal injection of cisplatin on day 14. Group III and IV were pretreated with two different doses of chrysin in addition to cisplatin and group V received chrysin only. Rats were examined for the effect of chrysin on cisplatin induced depletion of antioxidant enzymes, induction of lipid peroxidation and DNA damage in the kidney, utilizing a well-established model of cisplatin-induced nephropathy.. Pretreatment with chrysin significantly attenuated cisplatin-induced renal oxidative damage by diminishing the DNA damage and toxicity markers, such as creatinine and blood urea nitrogen, lipid peroxidation and xanthine oxidase activity, accompanied by increase in enzymatic (catalase, glutathione peroxidase, glutathione reductase and glutathione-S-transferase) and non-enzymatic (reduced glutathione) antioxidant status. Histological findings further substantiated the protective efficacy of chrysin, which reduced cisplatin-induced renal damage.. The data of the present study suggest that chrysin effectively suppress cisplatin-induced renal injury by ameliorating oxidative stress.

Topics: Animals; Anti-Inflammatory Agents; Antineoplastic Agents; Antioxidants; Biomarkers; Blood Urea Nitrogen; Cisplatin; Creatinine; DNA Damage; Flavonoids; Kidney; Kidney Diseases; Lipid Peroxidation; Male; Neoplasms; Oxidative Stress; Rats; Rats, Wistar; Reactive Oxygen Species; Renal Agents; Xanthine Oxidase

Chrysin exists widely in plants, honey and propolis. The anti-cancer property of chrysin has been demonstrated though the molecular mechanism is not clear. In this study, we found that pre-treatment with chrysin could promote the cell death induced by TRAIL according to the morphological changes and appearance of sub-G1 peak in four human cancer cell lines. In HCT-116 cells, the results of flow cytometry analysis showed that the percentage of sub-G1 reached (38.89 ± 3.78) % when pre-treatment of chrysin was used at 40 μM, but that was only (2.53 ± 0.10) % in the untreated group and (13.22 ± 0.20) % in TRAIL alone group. The differences between the combination and the untreated or TRAIL alone group were all significant (P<0.05) and dose-dependent effect was obvious. Similar results were obtained in CNE1 cells. In the search of molecular mechanisms, we found that pre-treatment with chrysin could increase TRAIL-induced degradation of caspase 3, caspase 8, PARP proteins. Z-VAD-fmk, which is a pan-caspase inhibitor, could inhibit the apoptosis enhanced by the combination of chrysin and TRAIL. All data indicate that chrysin can enhance the apoptosis induced by TRAIL, and the apoptosis is caspase-dependent and related to the activation of caspase 8.

Topics: Antineoplastic Agents; Apoptosis; Caspase 3; Caspase 8; Cell Survival; Drug Combinations; Drug Screening Assays, Antitumor; Drug Synergism; Flavonoids; HCT116 Cells; HeLa Cells; Hep G2 Cells; Humans; Neoplasms; TNF-Related Apoptosis-Inducing Ligand

The ubiquitin-proteasome pathway has an important role in regulating apoptosis and the cell cycle. The function of proteasomes is mediated by three main catalytic activities: (1) chymotrypsin-like (CT-L), (2) trypsin-like (T-L), and (3) peptidylglutamyl peptide hydrolyzing (PGPH). Recently, proteasome inhibitors have been revealed to have an antitumor effect, and have been used to treat cancers such as multiple myeloma. Previous studies have reported that some flavonoids can inhibit proteasome activity in tumor cells. To further investigate the proteasome-inhibitory mechanism of flavonoids, we examined the effects of the plant flavonoids apigenin, chrysin, and luteolin on the three individual catalytic activities in various cancer cell lines. Using fluorogenic substrates specific for proteasome catalytic subunits, we demonstrated the subunit specificity of each flavonoid. Addition of apigenin, chrysin and luteolin inhibited CT-L and T-L catalytic activities in a dose-dependent manner, whereas their effect on PGPH catalytic activity was weak. Our study suggested that these flavonoids have a specific role in inhibition of CT-L and T-L proteasome catalytic activities.

Topics: Antineoplastic Agents, Phytogenic; Apigenin; Cell Line, Tumor; Chymotrypsin; Dose-Response Relationship, Drug; Flavonoids; Humans; Hydrolysis; Luteolin; Neoplasms; Peptides; Plant Extracts; Proteasome Endopeptidase Complex; Trypsin; Ubiquitin

Chrysin (5,7-dihydroxyflavone) is a natural flavonoid commonly found in many plants. The anti-cancer property of chrysin has been demonstrated although the molecular mechanisms remain to be further elucidated. In the present study, we found that, pretreatment with chrysin greatly sensitized various human cancer cells to tumor necrosis factor-alpha (TNFalpha)-induced apoptosis. In the search of the molecular mechanisms responsible for the sensitization effect of chrysin, we discovered that such sensitization is closely associated with the inhibitory effect of chrysin on TNFalpha-mediated nuclear transcription factor-kappaB (NF-kappaB) activation. Pretreatment with chrysin inhibited TNFalpha-induced degradation of Inhibitor of kappaB (IkappaB) protein and subsequent nuclear translocation of p65. As a result, chrysin suppressed the expression of NF-kappaB-targeted anti-apoptotic gene, c-FLIP-L. The role of c-FLIP-L was further confirmed by its ectopic expression, which significantly protected cell death induced by combined treatment with chrysin and TNFalpha. Data from this study thus reveal a novel function of chrysin and enhance the value of chrysin as an anti-cancer agent.

Topics: Apoptosis; CASP8 and FADD-Like Apoptosis Regulating Protein; Colorectal Neoplasms; Down-Regulation; Drug Synergism; Flavonoids; HCT116 Cells; Hep G2 Cells; Humans; Immunoblotting; Liver Neoplasms; Nasopharyngeal Neoplasms; Neoplasms; NF-kappa B; Transfection; Tumor Necrosis Factor-alpha

In our study we used quercetin (3,3 ,4 ,5,7-pentahydroxyflavone) as the reference standard to compare antiproliferative and antiangiogenic effects of chrysin (5,7-dihydroxyflavone) and 3-hydroxyflavone. Our data indicates that chrysin and 3-hydroxyflavone showed significantly higher cytotoxic effect than reference standard quercetin. These tested agents significantly decreased cell survival with the efficacy of 65-85% at the concentration 100 micromol/l for HUVEC, lung carcinoma and leukemic cells being the most sensitive. Cell cycle analysis indicates that quercetin and 3-hydroxyflavone might affect the cell cycle of Jurkat cells by a similar or the same mechanism of action which lead to G2/M arrest as well as to an increase in sub-G0/G1 fraction. Treatment of Jurkat cells with chrysin resulted only increase in the fraction of cells with sub-G0/G1 DNA content, which is considered to be a marker of apoptotic cell death. Apoptosis was confirmed by DNA fragmentation and by staining with annexin V. All three tested flavones inhibited endothelial cell migration after 24 h of incubation at a concentration 100 micromol/l. At a lower concentration (10 micromol/l) only quercetin significantly inhibited migration of endothelial cells. Furthermore, in our experiments decreased secretion of matrix metalloproteinases (MMP-2 and MMP-9) was observed after a 72 h treatment with quercetin. No decrease in secretion of MMP-2 and MMP-9 was seen after chrysin and 3-hydroxyflavone treatment. On the other hand, our results showed that none of three flavonoids blocked microcapillary tube formation. Further studies are necessary to investigate the mechanism of action and to find out the relationship between the structure, character and position of substituents of natural substances and their biological activities.

Topics: Angiogenesis Inhibitors; Antineoplastic Agents; Apoptosis; Cell Cycle; Cell Line, Tumor; Cells, Cultured; DNA Fragmentation; Endothelial Cells; Flavones; Flavonoids; Humans; Matrix Metalloproteinase 2; Matrix Metalloproteinase 9; Neoplasms; Neovascularization, Pathologic; Quercetin