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ABSTRACT: Vitiligo is a pigmentation disorder in which inflammatory mediators such as cytokines have a pivotal role in disease's pathogenesis. Interleukin 17 (IL-17A) is a proinflammatory cytokine which is involved in the induction of several proinflamatory mediators such as cyclooxygenase 2 (COX2). The aim of this study was to investigate the gene expression of IL-17 and COX2 in peripheral blood leukocytes of vitiligo's patients. Peripheral blood leukocytes from 15 patients with vitiligo and 15 healthy controls were separated using a gradient density centrifugation method. After total RNA isolation and cDNA synthesis, IL-17 and COX2 gene expression were quantified by real-time polymerase chain reaction (PCR). There were no significant differences in IL-17 and COX2 gene expression in lymphocytes of patients with vitiligo compared with control group (p<0.05). However there was an increased IL-17 and COX2 gene expression in neutrophils of patients compared to controls, but it did not reach statistical significance (p=0.05). We could not find any differences in IL-17 and Cox2 gene expression between clinical diseases subtypes, sex and age. There was a significant correlation between IL-17 and COX2 genes expression in the neutrophils of patients (p=0.00, r=0.80). Our results showed an increased expression in IL-17 and Cox-2 genes in neurophils of patients with vitiligo. This suggested that these two factors are involved in the inflammatory process. Further studies with a larger sample size might help to establish the role of these factors in the pathogenesis of diseases.
IRANIAN JOURNAL OF ALLERGY, ASTHMA AND IMMUNOLOGY. All rights reserved. 05/2012;
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ABSTRACT: Recent studies have indicated a link between levels of cyclooxygenase-2 (COX-2) and development of the multidrug resistance (MDR) phenotype. The ATP-binding cassette sub-family G member 2 (ABCG2) is a major MDR-related transporter protein that is frequently overexpressed in cancer patients. In this study, we aimed to evaluate any positive correlation between COX-2 and ABCG2 gene expression using the COX-2 inducer 12-O-tetradecanoylphorbol-13-acetate (TPA) in human breast cancer cell lines. ABCG2 mRNA and protein expression was studied using real-time RT-PCR and flow cytometry, respectively. A significant increase of COX-2 mRNA expression (up to 11-fold by 4 h) was induced by TPA in MDA-MB-231 cells, this induction effect being lower in MCF-7 cells. TPA caused a considerable increase up to 9-fold in ABCG2 mRNA expression in parental MCF-7 cells, while it caused a small enhancement in ABCG2 expression up to 67 % by 4 h followed by a time-dependent decrease in ABCG2 mRNA expression in MDA-MB-231 cells. TPA treatment resulted in a slight increase of ABCG2 protein expression in MCF-7 cells, while a time-dependent decrease in ABCG2 protein expression was occurred in MDA-MB-231 cells. In conclusion, based on the observed effects of TPA in MDA-Mb-231 cells, it is proposed that TPA up-regulates ABCG2 expression in the drug sensitive MCF-7 breast cancer cell line through COX-2 unrelated pathways.
Asian Pacific journal of cancer prevention: APJCP 01/2012; 13(6):2979-84. · 0.66 Impact Factor
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ABSTRACT: The ATP-binding cassette sub-family G member 2 (ABCG2) is implicated as a member of multidrug resistant proteins in tumors, mediating efflux of a wide spectrum of anticancer drugs. Pro-inflammatory cytokines, which are present within the micro-environment of tumors and inflammation, are able to modulate the expressions and activities of different drug transporters. This study was aimed to evaluate the short-term (72-h treatment) effects of interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α), and interleukin-6 (IL-6) on the expression and function of ABCG2 in cervix carcinoma and gastric cancer cells. Effects of pro-inflammatory cytokines on mRNA, protein expression, and function of ABCG2 were studied using real time RT-PCR and flow cytometry methods, respectively. HeLa cells treated with IL-1β, IL-6, or TNF-α showed decrements in ABCG2 mRNA levels without any changes in protein expression and function of ABCG2. IL-6 and TNF-α had no effects on mRNA, protein expression, and function of ABCG2 in EPG85-257 cells. Although IL-1β did not alter ABCG2 at mRNA or protein levels in EPG85-257 cells, it augmented function of ABCG2 in these cells. Mitoxantrone accumulation was also amplified in IL-1β-, IL-6- or TNF-α-treated HeLa cells and in IL-1β-treated EPG85-257 cells. In conclusion, pro-inflammatory cytokines were able to modulate the expression of ABCG2 at transcriptional and post-transcriptional levels in human cervix and gastric cancer cells.
Molecular and Cellular Biochemistry 12/2011; 363(1-2):385-93. · 2.06 Impact Factor
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12/2011; , ISBN: 978-953-307-766-6
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ABSTRACT: Vitiligo is a pigmentation disorder in which inflammatory mediators such as cytokines have a pivotal role in disease's pathogenesis. Interleukin 17 (IL-17A) is a proinflammatory cytokine which is involved in the induction of several proinflamatory mediators such as cyclooxygenase 2 (COX2). The aim of this study was to investigate the gene expression of IL-17 and COX2 in peripheral blood leukocytes of vitiligo's patients.Peripheral blood leukocytes from 15 patients with vitiligo and 15 healthy controls were separated using a gradient density centrifugation method. After total RNA isolation and cDNA synthesis, IL-17 and COX2 gene expression were quantified by real-time polymerase chain reaction (PCR). There were no significant differences in IL-17 and COX2 gene expression in lymphocytes of patients with vitiligo compared with control group (p<0.05). However there was an increased IL-17 and COX2 gene expression in neutrophils of patients compared to controls, but it did not reach statistical significance (p=0.05). We could not find any differences in IL-17 and Cox2 gene expression between clinical diseases subtypes, sex and age. There was a significant correlation between IL-17 and COX2 genes expression in the neutrophils of patients (p=0.00, r=0.80). Our results showed an increased expression in IL-17 and Cox-2 genes in neurophils of patients with vitiligo. This suggested that these two factors are involved in the inflammatory process. Further studies with a larger sample size might help to establish the role of these factors in the pathogenesis of diseases.
Iranian journal of allergy, asthma, and immunology 06/2011; 10(2):81-9. · 0.51 Impact Factor
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ABSTRACT: In multidrug resistance (MDR), cancer cells exposed to anticancer agents develop resistance to a wide variety of chemicals and chemotherapeutic agents. Sesquiterpene coumarins are reported to inhibit P-glycoprotein and/or increase cytotoxicity of anticancer drugs in P-gp-overexpressing cell lines. In the current study, we investigated the effects of galbanic acid (from the roots of Ferula szowitsiana) and farnesiferol A (from the roots of Ferula persica) on functionality of the drug transporter P-glycoprotein (P-gp) using a rhodamine 123 efflux assay in a doxorubicin resistant breast cancer cell line (MCF7/Adr). Compared to verapamil, the well-known inhibitor of P-gp, galbanic acid (5, 10, and 25 µg/mL), significantly inhibited the P-gp activity. In inhibition of the P-gp transporter, farnesiferol A (0.5 µg/mL) was more potent than verapamil at 15 min exposure. Our results indicate that the plant derived sesquiterpene coumarins, farnesiferol A and galbanic acid, may be promising candidates to be considered for further studies on the reversal of multidrug resistance phenotype in chemotherapy of cancer patients.
Planta Medica 04/2011; 77(14):1590-3. · 2.15 Impact Factor
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ABSTRACT: Transitional cell carcinomas (TCCs), which account for 90% of bladder cancers, arise from the transitional epithelium of bladder. Cisplatin is a chemotherapeutic drug used to treat bladder cancer, but intrinsic and acquired resistance to cisplatin limit its effectiveness. The aim of this study was to determine the ability of mogoltacin, a sesquiterpene-coumarin from Ferula badrakema, to enhance cytotoxic effects of cisplatin on 5637 cells, using MTT assay, comet method, DAPI staining and efflux assay. In order to analyse mogoltacin combinatorial effects, 5637 cells were cultured in the presence of various combined concentrations of mogoltacin and cisplatin. The results of MTT assay revealed that combination of 1 μg/mL cisplatin+32 μg/mL mogoltacin, increased the cytotoxicity of cisplatin by 45.3%. Investigating the mechanism of this action by comet assay indicated that mogoltacin increases the apoptotic effects of cisplatin on 5637 cells via DNA lesion by 44%. Furthermore, studying nuclear morphological changes revealed that the combination of mogoltacin+cisplatin significantly (P<0.001) increases the number of apoptotic cells. Results of efflux assay indicated that mogoltacin did not have any significant effect on the activity of MDR transporters, therefore, this sesquiterpene-coumarin increases the effects of cisplatin possibly by interacting with other drug transporters.
Toxicology in Vitro 03/2011; 25(2):469-74. · 2.78 Impact Factor
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ABSTRACT: ABCG2 (BCRP) implicated as a member of the multidrug resistance (MDR) proteins in tumors, mediating efflux of a wide spectrum of anticancer drugs. In recent years, there has been an increasing tendency toward the exploring of the potential link between cyclooxygenase-2 (COX-2) expression and development of multidrug resistance phenotype in patients with cancer. The aim of this study was to investigate the role of the COX-2 in modulating drug efflux by ABCG2 in a group of breast cancer cell lines.
The cytotoxicity of COX-2 inducer (TPA, tetradecanoyl phorbol acetate) and its inhibitor (celecoxib) was determined by an MTT assay. ABCG2 activity was measured by flow cytometric mitoxantrone efflux assay.
TPA exhibited very little inhibitory activity in all cell lines, while long-term treatment with celecoxib significantly inhibited the growth of all cell lines. Furthermore, using mitoxantrone efflux assay was shown that TPA could increase ABCG2 activity in all the cell lines with the greatest stimulatory effects in MCF7-MX (more than 6 times the control level). It seemed that celecoxib inverted the effects of TPA on ABCG2 activity. This was more obvious in MCF7-MX.
The results suggest a probable causal link between COX-2 and ABCG2 activity. The use of celecoxib for adjuvant therapy in cancer treatment may contribute to decreased resistance to chemotherapeutic drugs transported by ABCG2.
Journal of Cancer Research and Clinical Oncology 02/2011; 137(2):321-30. · 2.56 Impact Factor
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ABSTRACT: Tumor necrosis factor alpha (TNF-α) has been reported to modulate the multidrug resistance (MDR) phenotype in vitro and in vivo. Multidrug-resistant cells overexpressing the ABCB1 transporter are more susceptible to inhibition of proliferation and induction of apoptosis by TNF-α than their drug-sensitive counterparts. This study was aimed to investigate TNF-α modulatory and antiproliferative effects on drug-resistant cells overexpressing ABCG2. The effects of TNF-α on viability and proliferation rate of MCF-7 breast cancer cells and their ABCG2-overexpressing sublines MCF-7/mitoxantrone (MX) cells were studied using dye exclusion assay, dimethylthiazolyl-2,5-diphenyl tetrazolium bromide technique, and flow cytometric analysis of cell cycle. TNF-α influence on MX accumulation was investigated by flow cytometry. ABCG2-overexpressing cells were more susceptible to antiproliferative and cytotoxic effects of TNF-α than their parental cells. TNF-α increased accumulation of MX in both parental and resistant cells. Higher sensitivity of MDR cells to TNF-α cytotoxicity would help in characterization of its complex modulatory effects on cancer cells and benefit us in designing new approaches to overcome MDR.
DNA and cell biology 02/2011; 30(6):413-8. · 2.28 Impact Factor
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ABSTRACT: Breast cancer resistance protein is a member of the ATP-binding cassette transporter G family that extrudes xenotoxins from cells, mediating drug resistance, and has been recognized as a major cause of failure of various carcinoma chemotherapies. In this study, the modulatory effects of dexamethasone and indomethacin on the cell cytotoxicity of mitoxantrone and on the BCRP protein activity in breast cancer cell lines were examined. MCF cells were seeded at 1 x 10(4) cells per well in 96-well flat-bottomed microplates for 48 hours and treated with increasing doses of dexamethasone, indomethacin, and novobiocin alone or preincubated with increasing doses of the drugs and then coexposed to mitoxantrone. Cell viability was measured after 1-4 days, using the MTT assay. BCRP activity was determined flow cytometrically by measuring mitoxantrone accumulation in the absence and presence of the inhibitor, novobiocin. Cotreatment of mitoxantrone with different concentrations of dexamethasone and indomethacin sensitized parental and resistant MCF-7 cells to mitoxantrone cytotoxicity. Dexamethasone increased the accumulation of mitoxantrone in the MCF-7/MX cell line, indicating an inhibition of BCRP. In spite of increased levels of mitoxantrone cytotoxicity in the presence of indomethacin, the accumulation of mitoxantrone was not increased in indomethacin-treated MCF cells.
Drug and Chemical Toxicology 04/2010; 33(2):113-9. · 1.08 Impact Factor
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ABSTRACT: Plants have been shown to possess a number of beneficial anticancer and immunomodulatory properties. In this study the possible in vitro antitumor activity and immunomodulatory effects of five species of Euphorbia, an important genus of Euphorbiaceae, including E. petiolata, E. hebecarpa, E. osyridea, E. microciadia, and E. heteradenia were investigated using cytotoxicity and cell proliferation assays. Among different tumor cell lines, the most sensitive cell line to methanolic extracts of the plants was determined as follows. Hela cervical cancer cells to E. hebecarpa and E. microciadia, K562 leukemia cells to E. petiolata and E. heteradenia, and Fen bladder cancer cells to E. osyridea. The methanolic extracts were then fractionated into hexane, n-butanol, ethyl acetate, and water and the effect of these fractions was tested for cytotoxic activity on the selected cell lines. The results indicated the significant stronger antiproliferatory effect of the hexane factions in all the plants when compared with other ones. The methanolic extracts of the plants were also studied for their effects on the activation of the lymphocytes. All of the extracts showed stimulatory effects on the proliferation of the lymphocytes at lower concentrations. After further fractionation of the extracts, the butanolic and hexane fractions showed the highest activity on the lymphocyte activation. In conclusion, all the plants studied had the capacity to inhibit proliferation of tumor cells with beneficial immunomodulatory effects on the lymphocytes. This dual effect of the plants indicates their value for further investigations as antitumor agents.
Immunopharmacology and Immunotoxicology 03/2010; 33(1):34-42. · 1.83 Impact Factor
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ABSTRACT: It is hypothesized that anti-inflammatory drugs regulate breast cancer resistance protein (BCRP) expression. Hence, we examined the effects of indomethacin and dexamethasone on BCRP expression in MCF cells. For evaluation of BCRP mRNA expression, relative quantitative PCR and comparative C1 method was exploited. BCRP protein expression was measured flow cytometrically with the monoclonal antibody (mAb) BXP-21. Dexamethasone showed a dose-independent and a time-dependent effect on decreasing the mRNA level of BCRP gene in comparison with control in MCF-7 and MCF-7/MX breast cancer cell lines, whereas no changes were noted in the presence of indomethacin. The level of BCRP protein, expressed as a ratio of the corresponding control, was decreased in dexamethasone-treated MCF-7/MX cells. These results could be of great importance when combination therapy protocols with cytotoxic agents and dexamethasone regimens are considered in breast cancer patients.
Oncology Research Featuring Preclinical and Clinical Cancer Therapeutics 01/2009; 18(1):9-15. · 1.30 Impact Factor
