Exploring the Synergistic Effect of Sildenafil and Green Tea Polyphenols on Breast Cancer Stem Cell-like Cells and their Parental Cells: A Potential Novel Therapeutic Approach.

BACKGROUND: Many cancer studies have intensely focused on the role of diet, among other factors involved in cancer establishment. The positive effect of green tea polyphenols (GTP) on controlling breast cancer cells has been reported in several studies. Cancer stem cell-like cells (CSC-LCs) possessing self-renewal, metastatic, and drug-resistant capacities are considered prominent therapeutic targets. In many tumors, inducible nitric oxide synthase (iNOS) expression levels are high; however, they have a dual effect on breast cancer pathogenesis. OBJECTIVE: This study aimed to investigate the cytotoxicity of the iNOS agonist (Sildenafil) and antagonist (LNAME), both alone and in combination with GTP, on MDA-MB-231, CD44+/CD24- CSC-LCs, and their parental cells (MCF-7). METHODS: The cell viability assay has been studied using the MTT assay. To analyze drug-drug combinations, CompuSyn and Combenefit software were used. The cytotoxicity mechanism was determined using flow cytometric analysis. RESULTS: L-NAME and GTP showed a synergistic effect on MDA-MB-231 and CSC-LCs. Such an effect was not observed on MCF-7. Sildenafil and GTP, on the other hand, showed synergistic cytotoxicity in all the cells mentioned above. Flow cytometric tests resulted in more than 70% apoptosis in MDA-MB-231 and MCF-7. Also, sub-G1 arrest among MCF-7 cells and a considerable decrease in ROS production by MDA-MB-231 cells following treatment with Sildenafil and GTP were observed. CONCLUSION: Sildenafil, in combination with flavonoids, may be considered a novel strategy for cancer treatment.

Synthesis, Biological Evaluation and Docking Study of New Pyrimidine Compounds as Anticancer Agents.

OBJECTIVES: The microtubule is composed of αß tubulin heterodimers and is an attractive target for the design of anticancer drugs. Over the years, various compounds have been developed and their effect on tubulin polymerization has been studied. Despite a great efforts to make an effective drug, no drug has been introduced which inhibit Colchicine binding site. METHODS: In the current work a series of pyrimidine derivatives were designed and synthesized. Furthermore their cytotoxic activities were evaluated and molecular docking studies were performed. Twelve compounds of pyrimidine were synthesized in 3 different groups. In the first group, 4,6-diaryl pyrimidine was connected to the third aryl group via thio-methylene spacer. In the second group, this linker was substituted by sulfoxide-methylene moiety and in the third group sulfone-methylene group was used as spacer. RESULTS: The cytotoxic activity of these compounds were evaluated against 3 different cancerous cell lines (HT-29, MCF-7, T47D) as well as normal cell line (NIH3T3). Compounds in group 2 showed the best cytotoxicity and compound 7D: showed the most potent cytotoxic activity against all cell lines. Molecular modelling studies revealed that compound 7D: could strongly bind to the colchicine binding site of tubulin. CONCLUSION: Altogether, with respect to obtained results, it is attractive and beneficial to further investigation on pyrimidine scaffold as antimitotic agents.

Design, Synthesis and Anticancer Evaluation of Novel Series of Indibulin Analogues.

BACKGROUND: Cancer is an important cause of human death worldwide. During the last decades, many anticancer agents with anti-tubulin mechanism have been synthesized or extracted from nature and some of them also entered clinical use. Indibulin is one of the most potent tubulin polymerization inhibitors with minimal peripheral neuropathy, which is a big problem by some of the antimitotic agents such as taxanes and vinka alkaloids. With respect to this giant benefit, herein we decided to design and synthesize novel indibulin related compounds and investigate their anticancer activity against HT-29, Caco-2 and T47-D cancerous cell lines as well as NIH-T3T as normal cell line. OBJECTIVE: The aim of this study was to synthesize new anti-cancer agents and evaluates their cytotoxic activity on diverse cancerous and normal cell lines. METHOD: Target compounds were synthesized in multistep reaction and cytotoxic activity was investigated by MTT cell viability assay. RESULTS: Herein, nine novel target compounds were synthesized in moderate to good yield. Some of the compounds exerted good cytotoxic activity against cancerous cell lines. Annexin V/PI staining showed that compound 4g could induce apoptosis and necrosis in HT-29 cell line. CONCLUSION: It is valuable to do further investigation on compound 4g which showed the highest activity against HT-29 and Caco-2 (IC50 values are 6.9 and 7 µM respectively). Also, synthesis of new derivatives of current synthesized compounds is suggested.

Pomegranate juice (punica granatum): a new storage medium for avulsed teeth.

OBJECTIVE: There is evidence indicating that pomegranate juice contains many of the essential properties necessary to retain cell viability and cell proliferation. These properties indicate that pomegranate juice is a suitable storage medium for avulsed teeth. However, this idea has not yet been tested. In this study, the capacity of pomegranate juice (PJ) as a storage medium for retaining avulsed teeth was evaluated. MATERIALS AND METHODS: PDL fibroblasts were obtained from healthy human premolars and cultured in Dulbecco's Modified Eagle's Medium (DMEM). Cultured cells were subjected to different concentrations of pomegranate juice (PJ), 1% Hank's balanced salt solution (HBSS) and tap water for 1, 3, 6 and 24 hours. PDL cell viability was assessed by the neutral red uptake assay. RESULTS: The results indicated that 7.5% PJ was the most effective solution for maintaining PDL cell viability amongst all the experimental solution's and time intervals (P<0.05). The results also showed that 1% PJ was as effective as HBSS for maintaining PDL cell viability. The amount of cell viability increased with increasing concentration of PJ at all time intervals (P<0.001). This effect is suggestive of the proliferative potential of PJ solution. CONCLUSION: In conclusion, PJ can be recommended as a suitable transport medium for avulsed teeth.

Evaluation of anti-invasion effect of cannabinoids on human hepatocarcinoma cells.

CONTEXT: Cancer is a disease characterized by abnormal growth of cells. One of the most common types of liver cancers is called hepatocellular carcinoma (HCC) which is highly metastatic. As most of cannabinoids have shown anticancer effect against different cell lines in a number of reports, a biological investigation of two cannabinoids, CB65 (CB2 receptor agonist) and ACEA (CB1 receptor agonist) was carried out in this study. OBJECTIVE: In an attempt to find natural products as a new solution of cancer, this study was designed to investigate the potential antitumoral and anti-invasive activity of cannabinoids on HepG2 cells and the possible roles of matrix metalloproteinase-2 (MMP-2) and MMP-9 in its action. MATERIALS AND METHODS: The researchers examined the effect of various concentrations of CB65 (CB2 receptor agonist) and ACEA (CB1 receptor agonist), on the cell proliferation, viability, and invasion as well as expression of MMP-2 and MMP-9 in HepG2 cells using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazoliumbromide (MTT) assay, matrigel invasion assay, and western blotting method. RESULTS: The results revealed that both cannabinoids reduce cell viability, cell invasion as well as MMP-2 and MMP-9 expression in higher dose of 20 nM. Furthermore, higher concentrations of examined cannabinoids were more effective. DISCUSSION: These data suggest ACEA and CB65 as an option for novel treatment of hepatocellular cancer. CONCLUSION: Our findings may contribute to design of new therapeutic strategies for the management of HCC.

Evaluation of the cytotoxicity of Satureja spicigera and its main compounds.

Satureja spicigera (Lamiaceae) grows wildly in Northwest of Iran. In this study, bioassay-guided isolation and identification of the main compounds has been reported using various chromatographic methods and comparison of their spectral data with those reported in the literature. Brine shrimp lethality and four cancerous cell lines HT29/219, Caco(2), NIH-3T3, and T47D were used for cytotoxicity evaluations. From the aerial parts of S. spicigera, nine known compounds including two flavanones, 5,7,3',5'-tetrahydroxy flavanone (8) and 5,4'-dihydroxy-3'-methoxyflavanone-7-(6''-O-α-L-rhamnopyranosyl)-ß-D-glucopyranoside (9), one dihydrochalcone, nubigenol (7), together with thymoquinone (1), thymol (2), carvacrol (3), ß-sitosterol (4), ursolic acid (5) and oleanolic acid (6) were identified. Among the isolated chalcone and flavanones, compound 8 was effective against Artemia salina larva (LC(50)= 2 µg/mL) and only the compound 9 demonstrated IC(50) value of 98.7 µg/mL on the T47D (human, breast, ductal carcinoma). Other compounds did not show significant inhibition of the cell growth.

Cytotoxicity of fucosterol containing fraction of marine algae against breast and colon carcinoma cell line.

CONTEXT: Marine algae produce different secondary metabolites with a wide range of biological activities. Many studies have been achieved on the screening of biological effects of marine organisms and a lot of active compounds were isolated and characterized. AIMS: In an attempt to find cytotoxic compound of hexane fraction, isolation, identification, and cytotoxicity of active compound of this fraction were performed. MATERIALS AND METHODS: In this study, total methanolic (70%) extract and partition fractions of hexane, chloroform (CHCl(3)), ethyl acetate (EtOAc), and MeOH-H(2)O of Sargassum angustifolium, Chondria dasyphylla, and Ulva flexuosa, collected from coastlines of the Persian Gulf in south of Iran, were studied against colon carcinoma (HT-29), colorectal adenocarcinoma (Caco-2), breast ductal carcinoma (T47D), and Swiss mouse embryo fibroblast (NIH 3T3) cell lines by MTT assay. STATISTICAL ANALYSIS USED: IC(50) (median growth inhibitory concentration) values were calculated by Sigmaplot (10) software. RESULTS: Hexane fraction of Chondria dasyphylla (IC(50) 82.26 ± 4.09 µg/ml) and MeOH-H(2)O fraction of Ulva flexuosa (IC(50) 116.92 ± 8.58 µg/ml) showed cytotoxic activity against proliferation of T47D cells. Hexane fraction of Sargassum angustifolium was also observed for cytotoxicity against T47D and HT-29 cell lines (IC(50) 166.42 ± 26.7 and 190.24 ± 52.8 µg/ml), respectively. An investigation of a component from the hexane fraction of Sargassum angustifolium yielded a steroidal metabolite, fucosterol, with cytotoxicity in T47D and HT29 (IC(50) 27.94 ± 9.3 and 70.41 ± 7.5 µg/ml). CONCLUSIONS: These results indicated that fucosterol, the most abundant phytosterol in brown algae, is responsible for cytotoxic effect of this extract against breast and colon carcinoma cell lines.

Investigation of selective cytotoxicity and determination of ligand induced apoptosis of a new acenaphtho [1,2-b] quinoxaline derivative.

Several new acenaphtho[1,2-b]quinoxaline derivatives were prepared by the reaction of o-phenylenediamines with acenaphthenequinones. The response of different carcinoid cell lines to these compounds were evaluated by MTT (3-(4,5-dimethylthiazol-2-yl)2,5-diphenyl tetrazolium bromide) assay and trypan blue exclusion tests. The cytotoxicity of 3,4-dinitroacenaphtho[1,2-b]quinoxaline (IIId) on the tested cell lines was confirmed by both tests. Furthermore, the MTT test showed a significant difference (p < 0.05) between the cytotoxicity of this compound on malignant cell lines of Caco-2, HT-29, T47D and non malignant mouse fibroblast cell line of NIH-3T3. An apoptosis inducing effect of compound IIId on K562 cells was detected by flow cytometry using Annexin-V-fluorescein isothiocyanate (AnV-FITC) and propidium iodide (PI) staining. The apoptosis induction (PI-/AnV+) in treated K562 cells was significantly (p < 0.01) more at 0.5 microg/ml concentration of compound IIId in comparison to all other concentrations of this compound and also doxorubicin (CAS 25316-40-9) (250 nM).