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Background and Objective: Curcumin is an effective anti-cancer agent used in thyroid cancer treatments. However, its use in clinical applications is limited due to low solubility and bioavailability. In this study, a novel combination strategy was applied by combining curcumin with Suberoylanilide Hydroxamic Acid (SAHA) to increase both bioavailability of curcumin and the efficiency of SAHA, which have limited efficiency when used alone. Methods: MTT assay was used to determine the cell viability of B-CPAP cells upon treatment with SAHA, curcumin and their combinations. Synergistic interactions between two agents were analyzed by Calcusyn software. Apoptosis and cell cycle assays were measured by flow cytometry. Expressions of apoptotic and cell cyclerelated proteins (PARP, P21/CDKN1A/WAF1, P27/KIP1) were examined by western blot analysis. Broth microdilution assay was performed to determine Minimum Inhibitory Concentration (MIC) values against S. aureus. Results: Based on MTT assay, IC50 values for SAHA and curcumin were determined as 0.91μM and 20.97μM, respectively. The combination index CI value was determined as 0.891 in B-CPAP cells, which demonstrate synergistic activity. The apoptotic effect was achieved by combination treatment (51.85%) on B-CPAP cells using half of the dose required for SAHA and curcumin alone. Combination treatment showed a significant increase in the percentage of B-CPAP cells in the S-phase due to cell arrest. Cleaved-PARP, P21/CDKN1A/ WAF1 and P27/KIP1 protein expressions were upregulated. Curcumin was found to have better anti-microbial activity than SAHA as having a lower MIC value, and checkerboard synergy analysis revealed that the two compounds co-operate synergistically for the in vitro killing of S. aureus. Conclusion: In the present study, synergistic combinations of SAHA and curcumin were shown to have both anti-cancer and antibacterial activities that would provide a novel thyroid cancer treatment strategy.

Background: Different cellular responses influence the progress of cancer. In this study, the effects of hydrogen peroxide and quercetin induced changes on cell viability, apoptosis, and oxidative stress in human hepatocellular carcinoma (HepG2) cells were investigated. Methods: The effects of hydrogen peroxide and quercetin on cell viability, cell cycle phases, and oxidative stress related cellular changes were investigated. Cell viability was assessed by WST-1 assay. Apoptosis rate, cell cycle phase changes, and oxidative stress were measured by flow cytometry. Protein expressions of p21, p27, p53, NF-Kβ-p50, and proteasome activity were determined by Western blot and fluorometry, respectively. Results: Hydrogen peroxide and quercetin treatment resulted in decreased cell viability and increased apoptosis in HepG2 cells. Proteasome activity was increased by hydrogen peroxide but decreased by quercetin treatment. Conclusion: Both agents resulted in decreased p53 protein expression and increased cell death by different mechanisms regarding proteostasis and cell cycle phases.

Flavonoids are phenolic substances with chemo-preventive and chemotherapeutic properties. They are widely found in fruits and vegetables. The polyphenols quercetin and curcumin have antioxidant, anti-inflammatory, anti-carcinogenic, and pro-apoptotic properties. They were successfully used against different human cancers, especially chronic myeloid leukemia cancer cells. We have previously investigated anti-proliferative and apoptotic effects of quercetin and curcumin combination in K562 cells. Our data showed that they had beneficial synergistic effects. Based on these findings, we aimed to clarify signaling pathways involved in synergistic combination treatment with quercetin and curcumin in these cells. Proteins were investigated by Western blotting and by confocal microscopy. Changes in several genes in 10 different pathways related to cell proliferation, apoptosis, cell cycle, inflammation, hypoxia and oxidative stress were observed. Combination of quercetin and curcumin was effective on genes that were particularly related to p53, NF-kappa B and TGF-alpha pathways. Down-regulatory (CDKN1B, AKT1, IFN-gamma) and up-regulatory (BTG2, CDKN1A, FAS) effects on genes and related protein expressions may provide a multi-targeted therapy potential for chronic myeloid leukemia cancer cells without affecting healthy cells.

Summary Background Walnuts contain many components including specific fatty acids, which could be active against cancer. Even though the anticarcinogenic effect of some of the individual fatty acids in walnut oil has been described, the effect of walnut oil itself on esophageal cancer cells hasn't yet been investigated. Objective We aimed to investigate whether walnut oil affects tumor growth and metastatic potential in esophageal cancer cells. Methods The human esophageal adenocarcinoma cell line, OE19, was treated with different doses of walnut oil and cell viability, apoptosis/necrosis and cell cycle analyses were performed using WST-1 assay and flow cytometry respectively. Adhesion, colony formation and wound healing assays were performed to assess the antimetastatic effects of walnut oil. NFkB expression was evaluated with western blot analysis. Results Walnut oil decreased the cell viability of esophageal cancer cells in a dose-dependent manner. 20 mg/mL walnut oil reduced cell viability by ∼50% when compared with control. The analysis revealed that necrosis and accumulation of cells in G0/G1 phase was induced in the cells treated with high doses of walnut oil. It also down-regulated the protein levels of NFkB. Walnut oil suppressed the adhesion, migration and colony formation of the cells. Conclusions High-dose short-term administration of walnut oil reduces the cell viability and metastatic ability of esophageal cancer cells, while exhibiting anticarcinogenic effect by inducing necrosis and cell cycle arrest at the G0/G1 phase, probably through suppression of the NFkB pathway. These data indicate that walnut oil, and by extension walnut consumption, may have beneficial effects in esophageal cancer in humans. This should be tested by clinical trials in the future.

In both healthy cells and cancer cells a number of different cellular responses influence the progress of cancer. In this study, we have investigated the effect of stress conditions on human hepatocyte cancer cells. Different concentrations of hydrogen peroxide, quercetin and N-acetyl cysteine were used to induce the acute cell stress. We have detected apoptosis, measured proteasome activity and performed a cell death array in both treated and control cells. Treatment of human hepatocyte cancer cells with hydrogen peroxide and quercetin resulted in decreased cell viability and increased apoptosis. On the other hand, proteasome activity was increased with hydrogen peroxide treatment but decreased with quercetin. N-acetyl cysteine supported cell viability and increased proteasome activity. In conclusion, cell death related genes were affected in quite different manner following hydrogen peroxide, quercetin and N-acetyl cysteine treatments.

Flavonoids have chemo-preventive and chemotherapeutic properties against different human cancers including chronic myeloid leukemia. Quercetin and curcumin are two polyphenols with potential anti-carcinogenic and pro-apoptotic properties. We have previously demonstrated the synergistic protective effect of quercetin and curcumin on chronic myeloid leukemia cells (K562) cells. Anti-proliferative and apoptotic effects of these polyphenols were examined by apoptosis and cell viability assays. Oxidative status of the cells was analyzed by determining the level of reactive oxygen species, mitochondrial permeability and intracellular glutathione. Obtained data showed that quercetin and curcumin had beneficial and synergistic effects on K562 cells. On the basis of the above-mentioned data, herein we aimed to clarify signaling pathways involved in synergistic combination of quercetin and curcumin on K562 cells. Normal peripheral blood mononuclear cell line was used as controls. The mRNA and protein expressions of the signaling pathways were detected by Human Signal Transduction Pathway Finder-RT2 PCR Array system and Western blotting, respectively. The results of PCR array were evaluated by DAVID v6.8 and database for KEGG pathways. Our data revealed that synergistic combination of curcumin quercetin was effective on genes that were particularly related to P53, NF and TGF. We believe that our findings will lead to new research in this area and will contribute to the chronic myeloid leukemia treatment protocols.

In this study, we have investigated the antiproliferative effect of quercetin on human papillary thyroid cancer cells and determined the apoptotic mechanisms underlying its actions. We have used different concentrations of quercetin to induce apoptosis and measured cell viability. Apoptosis and cell cycle analysis was determined by flow cytometry using Annexin V and propidium iodide. Finally, we have measured changes in caspase-3 and cleaved poly(ADP-ribose) polymerase (PARP) protein expression levels as hallmarks of apoptosis and Hsp90 protein expression level as a marker of proteasome activity in treated and control cells. Quercetin treatment of human papillary thyroid cancer cells resulted in decreased cell proliferation and increased rate of apoptosis by caspase activation. Furthermore, it was demonstrated that quercetin induces cancer cell apoptosis by downregulating the levels of Hsp90. In conclusion, we have shown that quercetin induces downregulation of Hsp90 expression that may be involved in the decrease of chymotrypsin-like proteasome activity which, in order, induces inhibition of growth and causes cell death in thyroid cancer cells. Thus, quercetin appears to be a promising candidate drug for Hsp90 downregulation and apoptosis of thyroid cancer cells.

Chronic myeloid leukemia is a major hematopoietic malignancy characterized by expansion of myeloid cells. In this study, we have investigated whether quercetin, curcumin and their combination induce apoptosis and inhibit growth of K562 cells. We have observed that quercetin and curcumin combination induced apoptosis accompanied by increased ROS and decreased GSH levels as well as loss of mitochondrial membrane potential. Our mRNA and protein expression results suggested that cytochrome c was released from mitochondria causing PARP and caspase-9 cleavages, the hallmarks of mitochondrial apoptotic pathway. We believe that triggering of apoptosis is mostly via mitochondrial pathway and ROS generation may induce impairment of mitochondrial membrane potential. The use of quercetin and curcumin combination potentiates individual apoptotic effects of the polyphenols and reduces their effective dose thereby preventing potential toxic effects on normal cells. Additional preclinical studies and clinical trials are certainly required to further validate their usefulness as potent anticancer agents.

Proteasomal degradation is an important target in cancer therapy. Many inhibitors have been developed and bortezomib and carfilzomib are used in the clinics. Glioblastoma is a grade IV astrocytoma, and the treatment procedure is radiotherapy and temozolomide combination following surgery. But many cases show drug resistance and recurrence. Recently glioblastoma stem cells, with high protesome activity, were found to be responsible for the drug resistance. In this study, we developed a 3D culture model of glioblastoma and we tested bortezomib and carfilzomib in combination with temozolomide. Hybrid 3D nanofiber scaffold were prepared by electrospinning of core-shell poly(e-caprolactone) (PCL)- bacterial cellulose and PCL- hyaluronic acid. Morphological, surface, and mechanical structure of 3D scaffold were characterized. Attachment of glioblastoma on the scaffold was confirmed by electron microscopy. Temozolomide, bortezomib and carfilzomib treatments were performed on the cell attached scaffolds. Proteasome inhibition, cell viability and apoptosis were tested. Data showed that combination of bortezomib and carfilzomib with temozolomide increased the anti-tumor effects. According to our previous studies, carfilzomib with its lower side effects can be tried in the clinics.