chrysin and Lung-Neoplasms

Pancreatic adenocarcinoma (PDAC) and lung cancer are expected to represent the most common cancer types worldwide until 2030. Under typical conditions, mitochondria provide the bulk of the energy needed to sustain cell life. For that inhibition of mitochondrial complex ΙΙ (CΙΙ) and ubiquinone oxidoreductase with natural treatments may represent a promising cancer treatment option. A naturally occurring flavonoid with biological anti-cancer effects is chyrsin. Due to their improved bioavailability, penetrative power, and efficacy, chitosan-chrysin nano-formulations (CCNPs) are being used in medicine with increasing frequency. Chitosan (cs) is also regarded as a highly versatile and adaptable polymer. The cationic properties of Cs, together with its biodegradability, high adsorption capacity, biocompatibility, effect on permeability, ability to form films, and adhesive properties, are advantages. In addition, Cs is thought to be both safe and economical. CCNPs may indeed be therapeutic candidates in the treatment of pancreatic adenocarcinoma (PDAC) and lung cancer by blocking succinate ubiquinone oxidoreductase.

Topics: Adenocarcinoma; Adenocarcinoma of Lung; Chitosan; Flavonoids; Humans; Lung Neoplasms; Nanoparticles; Pancreatic Neoplasms; Succinate Dehydrogenase; Ubiquinone

The our previous study synthesized the chrysin-chromene-spirooxindole hybrids 3, and further found compound 3e had good antitumor activity against A549 cells in vitro through multi-target co-regulation of the p53 signalling pathway to inhibit the proliferation of A549 cells. This study was designed to evaluate the antitumor effects of compound 3e on Lewis lung carcinoma of C57BL/6 mice in vivo. Compound 3e significantly inhibited the growth of transplanted tumors in C57BL/6 mice and induced the apoptosis of tumor cells. Further studies showed that compound 3e activates and expands the anti-cancer activity of p53 by inhibiting the expression of MDM2, Akt and 5-Lox proteins, accordingly promotes the expressions Bax and inhibit the Bcl-2 protein, the release of Cyt c as well, which resulted in the activation of apoptotic pathway in tumor cells eventually. Moreover, Compound 3e inhibited tumor metastasis by down-regulating VEGF, ICAM-1 and MMP-2 protein expression and angiogenesis. These results suggested that compound 3e exerts an effective antitumor activity in vivo through activating the p53 signaling pathway, which could be exploited as a promising candidate for the development of new anti-tumour drugs.

Topics: A549 Cells; Animals; Antineoplastic Agents; Benzopyrans; Carcinoma, Lewis Lung; Down-Regulation; Drug Design; Flavonoids; Humans; Lung Neoplasms; Mice; Mice, Inbred C57BL; Oxindoles; Proto-Oncogene Proteins c-bcl-2; Signal Transduction; Tumor Suppressor Protein p53; Vascular Endothelial Growth Factor A; Xenograft Model Antitumor Assays

The aberrant expression of claudins (CLDNs), which are tight junctional proteins, is seen in various solid tumors, but the regulatory mechanisms and their pathophysiological role are not well understood. Both CLDN1 and CLDN11 were highly expressed in human lung squamous cell carcinoma (SCC). Chrysin, found in high concentration in honey and propolis, decreased CLDN1 and CLDN11 expression in RERF-LC-AI cells derived from human lung SCC. The phosphorylation level of Akt was decreased by chrysin, but those of ERK1/2 and c-Jun were not. LY-294002, an inhibitor of phosphatidylinositol 3-kinase, inhibited the phosphorylation of Akt and decreased the expression levels of CLDN1 and CLDN11. The association between phosphoinositide-dependent kinase 1 (PDK1) and Akt was inhibited by chrysin, but the phosphorylation of PDK1 was not. Immunoprecipitation and quartz-crystal microbalance assays revealed that biotinylated-chrysin binds directly to Akt. The knockdown of CLDN1 and CLDN11 using small interfering RNAs increased the transepithelial flux of doxorubicin (DXR), an anthracycline anticancer drug. Similarly, both chrysin and LY-294002 increased DXR flux. Neither CLDN1 knockdown, CLDN11 knockdown, nor chrysin changed the anticancer drug-induced cytotoxicity in a two-dimensional culture model, whereas they enhanced cytotoxicity in a spheroid culture model. Taken together, chrysin may bind to Akt and inhibit its phosphorylation, resulting in the elevation of anticancer drug-induced toxicity mediated by reductions in CLDN1 and CLDN11 expression in RERF-LC-AI cells. We suggest that chrysin may be useful as an adjuvant chemotherapy in lung SCC.

Topics: Adenocarcinoma of Lung; Antineoplastic Agents; Carcinoma, Squamous Cell; Cell Line, Tumor; Claudin-1; Claudins; Doxorubicin; Flavonoids; Gene Expression Regulation, Neoplastic; Humans; Lung Neoplasms; Phosphorylation

Docetaxel (DTX) is an effective commercial anticancer agent for chemotherapy in non-small cell lung cancer (NSCLC), breast cancer, gastric cancer, and prostate cancer, but its adverse effects including edema, neurotoxicity, and hair loss limit its application. To improve the chemotherapeutic efficacy of DTX and reduce adverse effects, combination therapy is one of the alternative methods. So chrysin, which has various biological activities including anticancer effects, was considered. In vitro, the combination of chrysin and DTX was investigated in A549 cells. Increased cytotoxicity, suppressed cellular proliferation, and induced apoptosis were observed with posttreatment of chrysin following DTX treatment. In vivo, chrysin enhanced the tumor growth delay of DTX and increased DTX-induced apoptosis in the A549-derived xenograft model. Furthermore, chrysin prevented DTX-induced edema in ICR mouse. These results indicated that chrysin strengthened the therapeutic efficacy of DTX and diminished the adverse effect of DTX, suggesting chrysin could be exploited as an adjuvant therapy for NSCLC.

Topics: A549 Cells; Animals; Antineoplastic Agents; Apoptosis; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Cell Proliferation; Docetaxel; Edema; Female; Flavonoids; Humans; Lung Neoplasms; Mice; Mice, Inbred BALB C; Mice, Inbred ICR; Taxoids; Xenograft Model Antitumor Assays

Chemoprevention is considered as one of the most promising and realistic approaches in the prevention of lung cancer. Chrysin, a naturally occurring dietary flavone widely found in Passiflora family of plants and honey, has been studied extensively for its chemopreventive properties. The objective of present study is to divulge the chemopreventive role of chrysin against benzo(a)pyrene [B(a)P] induced lung carcinogenesis in Swiss albino mice.. B(a)P was administered orally (50mg/kg body weight) twice a week for four weeks to induce lung cancer in mice. The body weight, lung weight, tumor incidence, lipid peroxidation, carcinoembryonic antigen, enzymatic antioxidants (superoxide dismutase, catalase, glutathione peroxidase, glutathione reductase) and non-enzymatic antioxidants (reduced glutathione, vitamin E and vitamin C) were estimated. Further, histopathological analysis of lung tissue and western blotting analysis of PCNA, COX-2 and NF-κB were also carried out.. Administration of B(a)P resulted in increased lipid peroxides and carcinoembryonic antigen with concomitant decrease in the levels of both enzymatic antioxidants and non-enzymatic antioxidants. Chrysin treatment (250mg/kg body weight) significantly attenuated all these changes thereby showing potent anti lung cancer effect. Further, the anticancer effect of chrysin was confirmed by histopathology of lungs, and immunoblotting analysis of PCNA, COX-2 and NF-κB, where chrysin supplementation downregulated the expression of these proteins and maintained cellular homeostasis.. Overall, these findings confirm the chemopreventive potential of chrysin against B(a)P induced lung cancer in Swiss albino mice.

Topics: Animals; Anticarcinogenic Agents; Antioxidants; Ascorbic Acid; Benzo(a)pyrene; Carcinogenesis; Catalase; Chemoprevention; Diet; Disease Models, Animal; Flavones; Flavonoids; Glutathione; Glutathione Peroxidase; Glutathione Reductase; Lipid Peroxidation; Lung; Lung Neoplasms; Male; Mice; NF-kappa B; Superoxide Dismutase; Vitamin E

Honey is reported to contain various compounds such as antioxidants. Chrysin is a natural and biologically active compound extracted from honey. It possesses antioxidant properties and promotes cell death by perturbing cell cycle progression. We focused on the possible role that chrysin may act as a potential anticancer agent, and tested its biological activity and possible mechanisms in the human lung adenocarcinoma epithelial cell line.. Antiproliferative effect of honey and chrysin were determined by 3-(4, 5-Dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT) assay; DNA fragmentation was determined by gel electrophoresis assay; apoptosis was detected by flow cytometer; apoptosis-related gene expression was detected by reverse transcription polymerase chain reaction assay; and activation of caspase-3 and caspase-9 were evaluated by a colorimetric assay; Bax and Bcl-2 protein expression were also analysed by western blotting.. The results revealed that the cell viability decreased in a concentration- and time- dependent manner in the malignant cells treated with honey and chrysin in comparison with the nonmalignant cells. The IC50 values of honey against A549 cells were determined 15 ± 0.05% and 8 ± 0.05 % after 48 and 72h, respectively. The IC50 dose of chrysin was determined to be 49.2 ± 0.6 and 38.7 ± 0.8 μM at 48 and 72 h, respectively. Reactivity with Annexin V fluorescence antibody and propidium iodide showed that chrysin induced apoptosis in the lung cancer cells (p<0.001). Moreover, chrysin treatment resulted in the activation of caspase-3 and - 9 and an increase in the Bax/Bcl-2 ratio (p<0.01). Bax protein expression was increased but Bcl-2 protein expression decreased in chrysin-treated cells .Chrysin inhibits the growth of the lung cancer cells by inducing cancer cell apoptosis via the regulation of the Bcl-2 family and also activation of caspase-3 and -9, which may, in part, explain its anticancer activity.. This study shows that chrysin could also be considered as a promising chemotherapeutic agent and anticancer activity in treatment of the lung cancer cells in future.

Topics: Adenocarcinoma; Adenocarcinoma of Lung; Antineoplastic Agents; Apoptosis; bcl-2-Associated X Protein; Caspases; Cell Proliferation; Cell Survival; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; Epithelial Cells; Flavonoids; Humans; Lung Neoplasms; Proto-Oncogene Proteins c-bcl-2; Structure-Activity Relationship; Tumor Cells, Cultured

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) selectively kills various types of cancer cells without harming normal cells, but TRAIL resistance has been frequently observed in cancer cells. Propolis (bee glue) is a material collected from various plants by honeybees and is a rich source of bioactive compounds, including the natural flavonoid chrysin, which possesses multiple anticancer effects. We investigated the mechanism underlying the TRAIL sensitization effect of chrysin, which is a major constituent of Thai propolis, in human lung and cervical cancer cell lines. Propolis extract and chrysin sensitizes A549 and HeLa human cancer cell lines to TRAIL-induced apoptosis. The TRAIL sensitization effect of chrysin is not mediated by inhibition of TRAIL-induced NF-κB activation or by glutathione depletion. Immunoblot analysis using a panel of anti-apoptotic proteins revealed that chrysin selectively decreases the levels of Mcl-1 protein, by downregulating Mcl-1 gene expression as determined by qRT-PCR. The contribution of Mcl-1 in TRAIL resistance was confirmed by si-Mcl-1 knockdown. Among signaling pathways that regulate Mcl-1 gene expression, only constitutive STAT3 phosphorylation was suppressed by chrysin. The proposed action of chrysin in TRAIL sensitization by inhibiting STAT3 and downregulating Mcl-1 was supported by using a STAT3‑specific inhibitor, cucurbitacin-I, which decreased Mcl-1 levels and enhanced TRAIL-induced cell death, similar to that observed with chrysin treatment. In conclusion, we show the potential of chrysin in overcoming TRAIL resistance of cancer cells and elucidate its mechanism of action.

Topics: Female; Flavonoids; Gene Expression Regulation, Neoplastic; Glutathione; HeLa Cells; Humans; Lung Neoplasms; Myeloid Cell Leukemia Sequence 1 Protein; NF-kappa B; Phosphorylation; Propolis; STAT3 Transcription Factor; TNF-Related Apoptosis-Inducing Ligand; Uterine Cervical Neoplasms

We hypothesized that flavonoid-induced glutathione (GSH) efflux through multi-drug resistance proteins (MRPs) and subsequent intracellular GSH depletion is a viable mechanism to sensitize cancer cells to chemotherapies. This concept was demonstrated using chrysin (5-25 μM) induced GSH efflux in human non-small cell lung cancer lines exposed to the chemotherapeutic agent, doxorubicin (DOX). Treatment with chrysin resulted in significant and sustained intracellular GSH depletion and the GSH enzyme network in the four cancer cell types was predictive of the severity of chrysin induced intracellular GSH depletion. Gene expression data indicated a positive correlation between basal MRP1, MRP3 and MRP5 expression and total GSH efflux before and after chrysin exposure. Co-treating the cells for 72 h with chrysin (5-30 μM) and DOX (0.025-3.0 μM) significantly enhanced the sensitivity of the cells to DOX as compared to 72-hour DOX alone treatment in all four cell lines. The maximum decrease in the IC(50) values of cells treated with DOX alone compared to co-treatment with chrysin and DOX was 43% in A549 cells, 47% in H157 and H1975 cells and 78% in H460 cells. Chrysin worked synergistically with DOX to induce cancer cell death. This approach could allow for use of lower concentrations and/or sensitize cancer cells to drugs that are typically resistant to therapy.

Topics: Antibiotics, Antineoplastic; ATP Binding Cassette Transporter, Subfamily B; Doxorubicin; Drug Resistance, Neoplasm; Flavonoids; Glutathione; Humans; Lung Neoplasms; Tumor Cells, Cultured

Here we show that chrysin induces growth inhibition and apoptosis in cultured lung cancer A549 cells, and activation of AMP-activated protein kinase (AMPK) may contribute to this process. Our Western-blots results demonstrated a significant AMPK activation after chrysin treatment in A549 cells. Inhibition of AMPK by shRNA-mediated gene silencing, or by its inhibitor, diminished chrysin-induced A549 cell growth inhibition and apoptosis. Forced activation of AMPK by introducing a constitutively active form of AMPKα (CA-AMPKα), or by its activators, mimicked chrysin's effect. For mechanism analysis, we found chrysin inhibited Akt/mammalian target of rapamycin (mTOR) activation, and knocking-down of AMPK by shRNA almost reversed this effect. Finally, we observed that a relative low dose of chrysin enhanced doxorubicin-induced AMPK activation to promote A549 cell apoptosis. Our study suggests that activation of AMPK by chrysin contributes to Akt suppression, growth inhibition and apoptosis in human lung cancer cells, and agents that could activate AMPK may serve as useful adjuvants for traditional chemotherapy against lung cancer.

Topics: AMP-Activated Protein Kinases; Antineoplastic Agents; Apoptosis; Cell Line, Tumor; Cell Proliferation; Chemotherapy, Adjuvant; Doxorubicin; Enzyme Activation; Flavonoids; Humans; Lung Neoplasms; Proto-Oncogene Proteins c-akt; TOR Serine-Threonine Kinases

5-allyl-7-gen-difluoromethoxychrysin (AFMC) is a novel synthetic analogue of chrysin that has been reported to inhibit proliferation in various cancer cell lines. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a promising anti-cancer agent.. The cytotoxicity of A549 and WI-38 cells were determined using colorimetry. Apoptosis was detected by flow cytometry (FCM) after propidium iodide (PI) fluorescence staining and agarose gel electrophoresis. Caspase activities were evaluated using enzyme-linked immunosorbent assay (ELISA).The expressions of DR4 and DR5 were analyzed using FCM and western blot.. Subtoxic concentrations of AFMC sensitize human non-small cell lung cancer (NSCLC) A549 cells to TRAIL-mediated apoptosis. Combined treatment of A549 cells with AFMC and TRAIL significantly activated caspase-3, -8 and -9. The caspase-3 inhibitor zDEVD-fmk and the caspase-8 inhibitor zIETD-fmk blocked the apoptosis of A549 cells induced by co-treatment with AFMC and TRAIL. In addition, we found that treatment of A549 cells with AFMC significantly induced the expression of death receptor 5 (DR5). AFMC-mediated sensitization of A549 cells to TRAIL was efficiently reduced by administration of a blocking antibody or small interfering RNAs against DR5. AFMC also caused increase of the Sub-G1 cells by TRAIL treatment and increased the expression levels of DR5 in other NSCLC H460 and H157 cell lines. In contrast, AFMC-mediated induction of DR5 expression was not observed in human embryo lung WI-38 cells, and AFMC did not sensitize WI-38 cells to TRAIL-induced apoptosis.. AFMC synergistically enhances TRAIL-mediated apoptosis in NSCLC cells through up-regulating DR5 expression.

Topics: Antibodies, Blocking; Apoptosis; Blotting, Western; Carcinoma, Non-Small-Cell Lung; Caspase Inhibitors; Caspases; Cell Line; Cell Line, Tumor; Cell Survival; Cysteine Proteinase Inhibitors; Drug Synergism; Enzyme Activation; Enzyme-Linked Immunosorbent Assay; Flavonoids; Humans; Lung Neoplasms; Receptors, TNF-Related Apoptosis-Inducing Ligand; RNA Interference; TNF-Related Apoptosis-Inducing Ligand

Dihydrodiol dehydrogenase (DDH) is a member of the aldo-keto reductases superfamily (AKR1C1-AKR1C4), which plays central roles in the metabolism of steroid hormone, prostaglandin and xenobiotics. We have previously detected overexpression of DDH as an indicator of poor prognosis and chemoresistance in human non-small lung cancer (NSCLC). We also found DDH expression to be closely related to chronic inflammatory conditions. The aim of this study was to investigate the links between inflammation, DDH expression and drug resistance in NSCLC cells. We showed that pro-inflammatory mediators including interleukin-6 (IL-6) could induce AKR1C1/1C2 expression in NSCLC cells and increase cellular resistance to cisplatin and adriamycin. This effect was nullified by Safingol, a protein kinase C inhibitor. Moreover, the expression of AKR1C1/1C2 was inversely correlated to NBS1 and apoptosis-inducing factor (AIF). We also showed that IL-6-induced AKR1C1/1C2 expression and drug resistance were inhibited by wogonin and chrysin, which are major flavonoids in Scutellaria baicalensis, a widely used traditional Chinese and Japanese medicine. In conclusion, this study demonstrated novel links of pro-inflammatory signals, AKR1C1/1C2 expression and drug resistance in NSCLC. The protein kinase C pathway may play an important role in this process. Overexpression of AKR1C1/1C2 may serve as a marker of chemoresistance. Further studies are warranted to evaluate wogonin and chrysin as a potential adjuvant therapy for drug-resistant NSCLC, especially for those with AKR1C1/1C2 overexpression.

Topics: 20-Hydroxysteroid Dehydrogenases; Apoptosis; Carcinoma, Non-Small-Cell Lung; Cell Cycle; Cell Line, Tumor; DNA Repair; Dose-Response Relationship, Drug; Doxorubicin; Drug Resistance, Neoplasm; Flavanones; Flavonoids; Humans; Hydroxysteroid Dehydrogenases; Interleukin-6; Lung Neoplasms

Adjuvant therapies that enhance the anti-tumor effects of cis-diammineplatinum(II) dichloride (cisplatin, CDDP) are actively being pursued. Growing evidence supports the involvement of mitochondrial dysfunction in the anti-cancer effect of cisplatin. We examined the potential of using selective flavonoids that are effective in depleting tumor cells of glutathione (GSH) to potentiate cisplatin-mediated cytotoxicity in human lung adenocarcinoma (A549) cells. We found that cisplatin (40 microM, 48-h treatment) disrupts the steady-state levels of mitochondrial respiratory complex I, which correlates with elevated mitochondrial reactive oxygen species (ROS) production and cytochrome c release. The flavonoids, 2',5'-dihydroxychalcone (2',5'-DHC, 20 microM) and chrysin (20 microM) potentiated the cytotoxicity of cisplatin (20 microM), which could be blocked by supplementation of the media with exogenous GSH (500 microM). Both 2',5'-DHC and chrysin were more effective than the specific inhibitor of GSH synthesis, L-buthionine sulfoximine (BSO, 20 microM), in inducing GSH depletion and potentiating the cytotoxic effect of cisplatin. These data suggest that the flavonoid-induced potentiation of cisplatin's toxicity is due, in part, to synergetic pro-oxidant effects of cisplatin by inducing mitochondrial dysfunction, and the flavonoids by depleting cellular GSH, an important antioxidant defense.

Topics: Adenocarcinoma; Antineoplastic Agents; Cell Line, Tumor; Chalcones; Cisplatin; Drug Synergism; Electron Transport Complex I; Flavonoids; Glutathione; Humans; Lung Neoplasms; Mitochondria; Reactive Oxygen Species