Phorbol ester TPA modulates chemoresistance in the drug sensitive breast cancer cell line MCF-7 by inducing expression of drug efflux transporter ABCG2

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 pathway

Crocin suppresses multidrug resistance in MRP overexpressing ovarian cancer cell line

Background Crocin, one of the main constituents of saffron extract, has numerous biological effects such as anti-cancer effects. Multidrug resistance- associated proteins 1 and 2 (MRP1 and MRP2) are important elements in the failure of cancer chemotherapy. In this study we aimed to evaluate the effects of crocin on MRP1 and MRP2 expression and function in human ovarian cancer cell line A2780 and its cisplatin-resistant derivative A2780/RCIS cells. Methods The cytotoxicity of crocin was assessed by the MTT assay. The effects of crocin on the MRP1 and MRP2 mRNA expression and function were assessed by real-time RT-PCR and MTT assays, respectively. Results Our study indicated that crocin reduced cell proliferation in a dose-dependent manner in which the reduction in proliferation rate was more noticeable in the A2780 cell line compared to A2780/RCIS. Crocin reduced MRP1 and MRP2 gene expression at the mRNA level in A2780/RCIS cells. It increased doxorubicin cytotoxicity on the resistant A2780/RCIS cells in comparison with the drug-sensitive A2780 cells. Conclusion Totally, these results indicated that crocin could suppress drug resistance via down regulation of MRP transporters in the human ovarian cancer resistant cell line

Telomere shortening associated with increased levels of oxidative stress in sulfur mustard-exposed Iranian veterans

Sulfur Mustard (SM) is the most widely used chemical weapon. It was used in World War 1 and in the more recent Iran-Iraq conflict. Genetic toxicity and DNA alkylation effects of SM in molecular and animal experiments are well documented. In this study, lymphocytic telomere lengths and serum levels of isoprostane F2α were measured using q-PCR and enzyme immunoassay-based methods in 40 Iranian veterans who had been exposed to SM between 1983-88 and 40 non-exposed healthy volunteers. The relative telomere length in SM-exposed individuals was found to be significantly shorter than the non-exposed individuals. In addition, the level of 8-isoprostane F2α was significantly higher in the SM-exposed group compared to controls. Oxidative stress can be caused by defective antioxidant responses following gene mutations or altered activities of antioxidant enzymes. Chronic respiratory diseases and infections may also increaseoxidative stress. The novel finding of this study was a the identification of ‘premature ageing phenotype’. More specifically, telomere shortening which occurs naturally with aging is accelerated in SM-exposed individuals. Oxidative stress, mutations in DNA repair genes and epimutaions may be among the major mechanisms of telomere attrition. These findings may help for a novel therapeutic strategy by telomere elongation or for validation of an exposure biomarker for SM toxicity

Celecoxib up regulates the expression of drug efflux transporter ABCG2 in breast cancer cell lines

Elevated expression of the drug efflux transporter ABCG2 seems to correlate with multidrug resistance of cancer cells. Specific COX-2 inhibitor celecoxib has been shown to enhance the sensitivity of cancer cells to anticancer drugs. To clarify whether ABCG2 inhibition is involved in the sensitizing effect of celecoxib, we investigated whether the expression of ABCG2 in breast cancer cell lines, could be modulated by celecoxib. The expression of the multidrug resistant gene (ABCG2) at mRNA and protein level was detected by real-time quantitative reverse transcription-polymerase chain reaction and flow cytometry analysis, respectively. Among three human breast cancer cell lines ABCG2 and COX-2 were highly expressed in MCF7-MX and MDA-MB-231 cells, respectively. The COX-2 inhibitor celecoxib up-regulated the expression of ABCG2 mRNA in MCF-7 and MCF7-MX cells, which was accompanied by increased ABCG2 protein expression. While celecoxib was able to block the 12-O-tetradecanoylphorbol-13-acetate (TPA)-mediated increase in COX-2 expression in MDA-MB-231 cells, it increased the expression of ABCG2 up to 4.27 times to the control level at mRNA level and with less intensity at protein level. Our findings provide evidence that celecoxib up-regulates ABCG2 expression in human breast cancer cells and proposed that ABCG2 is not involved in chemosensitizing effects of celecoxib

The effects of crocetin, extracted from saffron, in chemotherapy against the incidence of multiple drug resistance phenotype

Objective(s): Crocetin, one of the main substances of saffron extract, has anti-cancer effects. Drug resistance proteins (e.g. MRP1 and MRP2) are important reasons for the failure of cancer therapy. We intended to investigate the efficacy of crocetin on MRP1 and MRP2 activity in human ovarian cisplatin-resistant carcinoma cell line (A2780-RCIS).Materials and Methods: The cytotoxic effect of crocetin was evaluated by the MTT assay. The efficacy of crocetin on MRP1 and MRP2 expression at mRNA level was studied by real-time RT-PCR. The effect of crocetin on the activity of MRP transporters was determined by drug efflux assay.Results: Crocetin decreased cell proliferation in the A2780 (IC50: 183±7 µM) and A2780-RCIS (IC50: 316±9 µM). Crocetin decreased the expression level of MRP1 (22±2 %) and MRP2 (48±8 %) in A2780-RCIS and inhibited MRP pumps function directly in A2780 (44±1 %) and A2780-RCIS (88±10 %) and indirectly in A2780 (32±2 %) and A2780-RCIS (48±15 %) respectively. Conclusion: Our findings showed that crocetin could quench drug resistance through modulation of MRP transporters in the drug resistant human ovarian cancer cells

Recent advances in nanocarriers containing Bromelain: In vitro and in vivo studies

Medicinal products of plant origin have long been considered the most affordable and accessible sources to treat different health problems. Bromelain (Br) is a mixture of enzymes derived from pineapple (Ananas comosus L.) with a wide field of applications including medicine, health, food, and cosmetics. Br has various therapeutic effects, such as antimicrobial, antioxidant, anticancer, wound healing, burn treatment, pain relief, anti-inflammatory, inhibition of platelet aggregation, and fibrinolytic activity. On the other hand, most proteins are susceptible to denaturation and structural changes that may reduce their activities. Encapsulation of drug molecules into nanoparticles (NPs) could increase their stability, bioavailability, and overcome other challenges in drug delivery and therapy. This review aimed to highlight various Br nano-formulations approaches, toward the improvement of Br therapeutic efficiency