The interaction mechanism of candidone with calf thymus DNA: A multi-spectroscopic and MD simulation study.

In this investigation, the effects of candidone on the structure and conformation of DNA were evaluated by spectroscopic methods, molecular dynamics simulation, and molecular docking studies. Fluorescence emission peaks, ultraviolet-visible spectra, and molecular docking exhibited the complex formation between candidone and DNA in a groove-binding mode. Fluorescence spectroscopy results also showed a static quenching mechanism of DNA in the presence of candidone. Moreover, thermodynamic parameters demonstrated that candidone spontaneously bound to DNA with a high binding affinity. The hydrophobic interactions were the dominant forces over the binding process. Based on the Fourier transform infrared data candidone tended to attach to the A-T base pairs of the minor grooves of DNA. The thermal denaturation and circular dichroism measurements displayed that candidone caused a slight change in the DNA structure, which was confirmed by the molecular dynamics simulation results. According to the obtained findings from the molecular dynamic simulation, the structural flexibility and dynamics of DNA were altered to a more extended structure.

Anticancer Properties of Probiotic Saccharomyces boulardii Supernatant on Human Breast Cancer Cells.

Saccharomyces boulardii, a variety of S. cerevisiae, is used as a probiotic yeast in food and drug industries. However, S. boulardii is an opportunistic pathogen, and the supernatant of this organism has recently been recommended for its health-promoting benefits. Breast cancer is the most frequent cancer disease in women worldwide. The objective of this study was to investigate the effects of S. boulardii supernatant (SBS) on cell viability, inducing apoptosis and suppression of survivin gene expression in MCF-7 and MCF-7/MX as human non-drug-resistant and multidrug-resistant breast cancer cells respectively. The IC50 value of SBS against MCF-7 was calculated 1037, 542, and 543 µg/mL for 24, 48, and 72 h treatments, respectively. Also, this value against MCF-7/MX cells were measured 1242, 616, and 444 µg/mL after 24, 48, and 72 h respectively. We found that suppression of survivin gene expression should be one of the main molecular antitumor mechanisms which is contributed to apoptosis in breast cancer cells. However, anticancer activity of SBS was observed more efficient against MCF-7 than that against MCF-7/MX cells. SBS is suggested to be considered as one of the prospective anticancer drugs to treat human breast carcinoma. More investigations especially in vivo studies are strongly recommended to be implemented to characterize other antitumor mechanisms of SBS against breast carcinoma.

Improvement of cytotoxicity of mitoxantrone and daunorubicin by candidone, tephrosin, and bavachinin.

BACKGROUND: Flavonoids have been demonstrated to have the ability of sensitizing cancer cells to chemotherapy and inverse multidrug resistance via various mechanisms, such as modulating of pumps. The therapeutic effect of candidone, tephrosin, and bavachinin in treatment of cancer, particularly to overcome multidrug resistance (MDR) is largely unknown. The capacity of these agents in sensitization of MDR cells is investigated in the current work. METHODS AND RESULTS: We analyzed the impact of candidone, tephrosin, and bavachinin, as chemosensitizer on cell cytotoxicity, P-gp and ABCG2 mRNA expression level on two multidrug resistant cells, ABCG2 overexpressing human epithelial breast cancer cell line (MCF7/MX), and P-gp overexpressing human gastric adenocarcinoma cell line (EPG85.257RDB). The inhibitory concentration of 50% (IC50) of daunorubicin in EPG85.257RDB cells in combination with IC10 of Bavachinin, Tephrosin, and Candidone were 6159 ± 948, 4186 ± 665, 730 ± 258 nM, and this data in MCF7/MX cell were 1773 ± 534, 7160 ± 405 and 3340 ± 622 nM respectively. These three flavonoids dose-dependently decreased the viability of MCF7/MX and EPG85.257RDB and significantly (p < 0.05) decreased IC50 of daunorubicin and mitoxantrone except Tephrosin in MCF7/MX cells. Candidone and Bavachinin were the most potent chemosensitizer in EPG85.257RDB and MCF7/MX cells respectively. Flavonoids did not reduce mRNA expression of P-gp and ABCG2 after 72 h treatment, except Candidone in EPG85.257RDB and Bavachinin in MCF7/MX cells. CONCLUSIONS: This effect is not time-dependent, and flavonoids have their own patterns that are cell-dependent. In general, tephrosin, candidone, and bavachinin had the potential of sensitizing MDR cells to mitoxantrone and daunorubicin.

Probiotic Saccharomyces cerevisiae var. boulardii supernatant inhibits survivin gene expression and induces apoptosis in human gastric cancer cells.

Natural anticancer drug and compounds with other great benefits are of interest recently due to lower side effects than chemotherapy for cancer treatment and prevention. Different natural and synthetic drugs have been suggested to be used for treatment of gastric cancers, the second deadly cancer worldwide. The aim of this study was to investigate anticancer activity of SBS including inducing apoptosis and inhibition of survivin gene expression in gastric cancer cells. We evaluated cell viability, inducing apoptosis and change in survivin gene expression of EPG85-257P (EPG) and EPG85-257RDB (resistant to Daunorubicin, RDB) cell lines under exposure of SBS after 24, 48, and 72 hr. We found that SBS decreased cell viability, induced apoptosis, and reduced survivin gene expression in treated EPG and RDB cells (with the significant IC50 values of 387 and 575 µg/ml after 72 and 48 hr for EPG and RDB cells respectively). However, we observed SBS was more efficient to induce apoptosis in EPG than RDB cells. We strongly suggest SBS be considered as a prospective anticancer agent or in formulation of complementary medication to treat and prevent gastric cancers.

Characterization and Prospective Applications of the Exopolysaccharides Produced by Rhodosporidium babjevae.

Purpose: Due to the potential industrial and therapeutic applications of the yeast exopolysaccharides (EPSs), there has been an increasing demand to assess these biopolymers with improved characteristics. This study aimed to characterize the EPSs from Rhodosporidium babjevae (ATCC 90942 and IBRC-M 30088) as well as to evaluate their possible antioxidant, emulsifying and antiproliferative activities. Methods: Rhodosporidium babjevae was cultured for 5 days and following isolation of supernatant, EPSs precipitated with adding of cold absolute ethanol and freeze-dried. The EPSs chemical structure was determined by FT-IR, SEM, HPLC-SEC and GC-MS. Additionally the solubility, water holding capacity and emulsifying activity of EPSs were evaluated. In vitro, antioxidant activity was investigated against DPPH, superoxide and hydroxyl radicals. Finally the EPSs consequence on the cell proliferation of human breast adenocarcinoma (MCF-7) and Madin-Darby canine kidney (MDCK) cell lines was evaluated by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) test. Results: R. babjevae excreted 1.6±0.2 g/L of the EPSs. The EPSs had three fractions with molecular weights of 1.02 ×106 , 5×105 and 2×105 Da. Mannose and glucose were found as the main monosaccharides of the EPSs (84:16 mol%, respectively). The EPSs exhibited emulsifying activity on sun flower oil. The scavenging activities were found to be dose-dependent and higher than hyaluronic acid. Significant difference among the EPSs treatments on the proliferation of MCF-7 and MDCK cell lines was not observed (P>0.05). Conclusion: These results show the interesting potential of the EPSs from R. babjevae as biocompatible compounds for using in food and pharmaceutical fields.

Resistance of human primary mesenchymal stem cells to cytotoxic effects of nutlin-3 in vitro.

BACKGROUND: The small-molecule nutlin-3 was found to be an effective therapeutic compound and p53 activator, and acts as a murine double minute 2 antagonist, although these findings need to be clinically confirmed. The essential components of the bone marrow include mesenchymal stem cells (MSCs), which play a key role in protecting, regenerating, and proliferating hematopoietic stem cells (HSCs). This feature is vital for HSC after exposure to myelotoxic anticancer agents; nevertheless, the effects of nutlin-3 on MSCs remain to be disclosed. The present research study was conducted to examine the antiproliferative and proapoptotic effectiveness of nutlin-3 in bone marrow MSCs (BMSCs). MATERIALS AND METHODS: Human-derived BMSCs were cultured for different durations, that is, 24, 48, and 72 hours, and treated using various concentrations of nutlin-3, including 5, 10, 25, 50, and 100 µΜ. To investigate the effect of nutlin-3 on the apoptosis, cell vitality and proliferation in BMSCs, the terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL), thiazolyl blue tetrazolium bromide, propidium iodide (PI) and annexin V assay, as well as real-time polymerase chain reaction, were used. RESULTS: BMSCs viability significantly decreased (P < .05) in the cells treated at concentrations of 50 and 100 µM for 24 hours and concentrations of 25, 50, and 100 µM for 48 hours and at all concentrations for 72 hours. The apoptosis of BMSCs (TUNEL positive) was significantly more visible at concentrations of 25 and 50 µM compared with that in the controls (P < .05), while this increased through dose-dependent processes. Annexin V/PI staining revealed negligible dose-dependent increases in all the apoptotic cells after 72 hours of incubation, and this apoptosis elevation was significant at 25 and 50 µM (P < .05). CONCLUSION: Resistance to nutlin-3 was observed in human bone marrow-derived MSCs; nevertheless, further clinical data are required to be obtained with long-duration exposure to confirm the present findings.

Enhancing the Therapeutic Efficacy of Daunorubicin and Mitoxantrone with Bavachinin, Candidone, and Tephrosin.

The capability of flavonoids in sensitizing cancer cells was demonstrated in numerous works to chemotherapy and converse multidrug resistance by modulating efflux pumps and apoptosis mechanisms. Three flavonoids, namely, bavachinin, tephrosin, and candidone, have been recently introduced to cancer treatment research presenting various activities, such as antibacterial, immunomodulatory, cell death, and anticancer. Less information exists regarding the therapeutic significance of these flavonoids in cancer treatment, especially in overcoming multidrug resistance (MDR). Here, we tempted to investigate the potency of these agents in reversing MDR by analyzing their effects as chemosensitizers on cell cytotoxicity, P-gp and ABCG2 protein expression levels, and their function on two multidrug-resistant cell lines, P-gp-overexpressing human gastric adenocarcinoma cell line (EPG85.257RDB) and ABCG2-overexpressing human epithelial breast cancer cell line (MCF7/MX). The inhibitory concentration of 10% (IC10) of bavachinin, tephrosin, and candidone in EPG85.257RDB cells was 1588.7 ± 202.2, 264.8 ± 86.15, and 1338.6 ± 114.11 nM, respectively. Moreover, these values in MCF7/MX cell were 2406.4 ± 257.63, 38.8 ± 4.28, and 27.9 ± 5.59 nM, respectively. Expression levels of ABCG2 and P-gp were not significantly downregulated by these flavonoids. Maximum levels of daunorubicin and mitoxantrone accumulations and minimum rates of drug efflux in both cell lines were detected 48 hrs posttreatment with tephrosin and bavachinin, respectively. Chemosensitization to mitoxantrone and daunorubicin treatments was, respectively, achieved in MCF7/MX and EPG85.257RDB cells in response to IC10 of bavachinin and tephrosin, independently. These effects did not follow time-dependent manner, and each flavonoid had its cell-dependent patterns. Overall, bavachinin, tephrosin, and candidone showed potency to sensitize MDR cells to daunorubicin and mitoxantrone and could be considered as attractive MDR modulators for cancer treatment. However, their action was time and cell specific.