Synergistic effects of dendrosomal nanocurcumin and oxaliplatin on oncogenic properties of ovarian cancer cell lines by down-expression of MMPs.

BACKGROUND: Contrary to the advantageous anticancer activities of curcumin (Cur), limited bioavailability and solubility hindered its efficacy. Here, nontoxic dendrosomal nano carrier with Cur was used to overcome these problems. Despite considerable antitumor properties of Oxaliplatin (Oxa), the limiting factors are drug resistance and adverse side-effects. The hypothesis of this study was to evaluate the possible synergism between dendrosomal nanocurcumin (DNC) and Oxa and these agents showed growth regulatory effects on SKOV3 and OVCAR3 cells. METHODS AND MATERIALS: In the present study, colony formation, wound healing motility, cell adhesion, transwell invasion and migration assay and cell cycle arrest with or without DNC, Oxa and Combination were defined. In addition to, real time PCR and Western blot were used to analyze AKT, PI3K, PKC, JNK, P38 and MMPs mRNAs and proteins expressions. Docking of MMP-2-Cur, MMP-2-DNC and MMP-2-Oxa was performed and the results of all three complexes were simulated by molecular dynamics. RESULTS: Our findings illustrated that DNC had the greatest effect on cell death as compared to the Cur alone. Moreover, the growth inhibitory effects (such as cell death correlated to apoptosis) were more intense if Oxa was added followed by DNC at 4 h interval. However, insignificant effects were observed upon simultaneous addition of these two agents in both cell lines. Besides, a combination of agents synergistically alters the relative expression of MMP-9. CONCLUSIONS: The docking results showed that His70 and Asp100 may play a key role at the MMP-2 binding site. The matrigel invasion as well as cell viability of ovarian cancer cell lines SKOV3 and OVCAR3 by DNC alone or in combination with Oxa was inhibited significantly. The inhibitory effects of these agents were due to the differential expression levels of MMP 2 and MMP 9 regulated by multiple downstream signaling cascades. From the molecular dynamic simulation studies, it was confirmed that DNC established a strong interaction with MMP-2.

Effects of the exercise-inducible myokine irisin on proliferation and malignant properties of ovarian cancer cells through the HIF-1 α signaling pathway.

Exercise has been shown to be associated with reduced risk and improving outcomes of several types of cancers. Irisin -a novel exercise-related myokine- has been proposed to exert beneficial effects in metabolic disorders including cancer. No previous studies have investigated whether irisin may regulate malignant characteristics of ovarian cancer cell lines. In the present study, we aimed to explore the effect of irisin on viability and proliferation of ovarian cancer cells which was examined by MTT assay. Then, we evaluated the migratory and invasive abilities of the cells via transwell assays. Moreover, the percentage of apoptosis induction was determined by flow cytometry. Furthermore, the mRNA expression level of genes related to the aerobic respiration (HIF-1α, c-Myc, LDHA, PDK1 and VEGF) was detected by real-time PCR. Our data revealed that irisin treatment significantly attenuated the proliferation, migration and invasion of ovarian cancer cells. Additionally, irisin induced apoptosis in ovarian cancer cells. We also observed that irisin regulated the expression of genes involved in aerobic respiration of ovarian cancer cells. Our results indicated that irisin may play a crucial role in inhibition of cell growth and malignant characteristics of ovarian cancer. These findings may open up avenues for future studies to identify the further therapeutic use of irisin in ovarian cancer management.

Synergistic effects of dendrosomal nanocurcumin and oxaliplatin on oncogenic properties of ovarian cancer cell lines by down-expression of MMPs

BACKGROUND: Contrary to the advantageous anticancer activities of curcumin (Cur), limited bioavailability and solubility hindered its efficacy. Here, nontoxic dendrosomal nano carrier with Cur was used to overcome these problems. Despite considerable antitumor properties of Oxaliplatin (Oxa), the limiting factors are drug resistance and adverse side-effects. The hypothesis of this study was to evaluate the possible synergism between dendrosomal nanocurcumin (DNC) and Oxa and these agents showed growth regulatory effects on SKOV3 and OVCAR3 cells. METHODS: and materials In the present study, colony formation, wound healing motility, cell adhesion, transwell invasion and migration assay and cell cycle arrest with or without DNC, Oxa and Combination were defined. In addition to, real time PCR and Western blot were used to analyze AKT, PI3K, PKC, JNK, P38 and MMPs mRNAs and proteins expressions. Docking of MMP-2-Cur, MMP-2-DNC and MMP-2-Oxa was performed and the results of all three complexes were simulated by molecular dynamics. RESULTS: Our findings illustrated that DNC had the greatest effect on cell death as compared to the Cur alone. Moreover, the growth inhibitory effects (such as cell death correlated to apoptosis) were more intense if Oxa was added followed by DNC at 4 h interval. However, insignificant effects were observed upon simultaneous addition of these two agents in both cell lines. Besides, a combination of agents synergistically alters the relative expression of MMP-9. CONCLUSIONS: The docking results showed that His70 and Asp100 may play a key role at the MMP-2 binding site. The matrigel invasion as well as cell viability of ovarian cancer cell lines SKOV3 and OVCAR3 by DNC alone or in combination with Oxa was inhibited significantly. The inhibitory effects of these agents were due to the differential expression levels of MMP 2 and MMP 9 regulated by multiple downstream signaling cascades. From the molecular dynamic simulation studies, it was confirmed that DNC established a strong interaction with MMP-2.

Bioinformatic Investigation of Micro RNA-802 Target Genes, Protein Networks, and Its Potential Prognostic Value in Breast Cancer.

Background: An increasing number of studies have suggested that unveiling the molecular network of miRNAs may provide novel therapeutic targets or biomarkers. In this study, we investigated the probable molecular functions that are related to microRNA-802 (miR-802) and evaluated its prognostic value in breast cancer utilizing bioinformatics tools. Methods: PPI network, pathway enrichment and transcription factor analysis were applied to obtain hub genes among overlapping genes of four miRNA target prediction databases. Prognosis value assessments and expression analysis of hub genes using bioinformatics tools, as well as their literature validation were performed. Results: Our results showed a significant correlation of the miR-802 overexpression with poor patient survival rate (BC, p=2.7e-5). We determined 247 target genes significant for GO and KEGG terms. Analysis of TFs by TRUST showed that RUNX3, FOXO3, and E2F1 are possible TFs that regulate the miR-802 expression and target genes network. According to our analysis; 21 genes might have an important function in miR-802 molecular processes and regulatory networks. The result shows that among these 21 genes, 8 genes (CASC3, ITGA4, AGO3, TARDBP, MED13L, SF1, SNRPE and CRNKL1) are positively correlated with patient survival. Therefore these genes could be considered and experimentally evaluated as a prognostic biomarker for breast cancer. Conclusion: The comprehensive bioinformatics study on miR-802 target genes provided insight into miR-802 mediated pathways and processes. Furthermore, representing candidate target genes by prognostic values indicates the potential clinical application of miR-802 in breast cancer.

The Effect of Irisin on Proliferation, Apoptosis, and Expression of Metastasis Markers in Prostate Cancer Cell Lines.

INTRODUCTION: Irisin is a newly discovered myokine released from skeletal muscle during exercise. The matrix metalloproteinases (MMPs) are a family of proteolytic enzymes that play a key role in the metastatic process via degrading extracellular matrix. The aim of this study was to investigate the effect of irisin on expression of metastatic markers MMP2 and MMP9 and induced apoptosis in human prostate cancer cells. METHODS: In this study, we examined the effect of different concentrations of irisin on induced apoptosis and cell viability of two cell lines, LNCaP and DU-145, by using flow cytometry and MTT assay, respectively. The expression of MMP2 and MMP9 genes was also analyzed by real-time PCR after irisin treatment. Data were analyzed using the comparative cycle threshold 2-∆∆Ct method. RESULTS: Cell viability was reduced in both LNCaP and DU-145 cell lines at different concentrations of irisin. However, this decreased cell viability was strongly significant (p < 0.05) only at 5 and 10 nM concentrations of irisin in the LNCaP cell line. Furthermore, irisin could induce apoptosis in both cell lines at a concentration of 10 nM compared to 5 nM. Real-time PCR results also demonstrated a decreased expression in MMP2 and MMP9 genes in a concentration-dependent manner in both cell lines. CONCLUSION: These results showed the anticancer effects of irisin on cell viability of both LNCaP and DU-145 cell lines and also on the expression of MMP2 and MMP9 genes occurred in a dose- and time-dependent manner.

The impact of LncRNA dysregulation on clinicopathology and survival of pancreatic cancer: a systematic review and meta-analysis (PRISMA compliant).

PURPOSE: An increasing number of studies have reported a significant association between long non-coding RNAs (lncRNAs) dysregulation and pancreatic cancers. In the present study, we aimed to gather articles to evaluate the prognostic value of long non coding RNA in pancreatic cancer. EXPERIMENTAL DESIGN: We systematically searched all eligible articles from databases of PubMed, Web of Science, and Scopus to meta-analysis of published articles and screen association of multiple lncRNAs expression with clinicopathology and/or survival of pancreatic cancer. The pooled hazard ratios (HRs) and their 95% confidence intervals (95% CIs) were used to analysis of overall survival, disease-free survival and progression-free survival were measured with a fixed or random effects model. RESULTS: A total of 39 articles were included in the present meta-analysis. Our results showed that dysregulation of lncRNAs were linked to overall survival (39 studies, 4736 patients HR = 0.41, 95% CI 0.25 ± 0.58, random-effects in pancreatic cancer. Moreover, altered lncRNAs were also contributed to progression-free survival (8 studies, 1180 patients HR: 1.88, 95% CI (1.35-2.62) and disease-free survival (2 studies, 285 patients, HR: 6.07, 95% CI 1.28-28.78). In addition, our findings revealed the association between dysregulated RNAs and clinicopathological features in this type of cancer. CONCLUSIONS: In conclusion, dysregulated lncRNAs could be served as promising biomarkers for diagnosis and prognosis of pancreatic cancer.

The role of altered long noncoding RNAs in overall survival of ovarian cancer: A systematic review and meta-analysis.

In recent years, tremendous research efforts have been focused on investigating the effect of dysregulation of lncRNAs on cancer progression, most of which confirm a positive link. This inspired us to conduct the present meta-analysis to explore whether aberrant expression of multiple lncRNAs has a role in patients' outcome in ovarian cancer. This comprehensive meta-analysis pertains to the evaluation of association between dysregulated lncRNAs expression level with eventual outcome and clinicopathological characteristics of ovarian cancer patients. We systematically searched PubMed, Web of Science, and Scopus to find all eligible articles. Pooled hazard ratios (HRs) and 95% confidence intervals (95% CIs) for overall survival, disease-free survival and progression-free survival were measured with a fixed or random effects model. A total of 34 studies were included in the meta-analysis. Dysregulation of lncRNAs were contributed to shorter overall survival (34 studies, 1180 patients HR = 2.12, 95% CI: 1.73 ± 2.60, random-effects) in ovarian cancer. Furthermore, altered lncRNAs were also related to decreased progression-free survival (8 studies, 1180 patients HR: 1.88, 95% CI: (1.35-2.62) and disease-free survival (2 studies, 285 patients, HR: 6.07, 95% CI: 1.28-28.78) in this disease. Our analyses supported the robust prognostic significance of altered lncRNAs in ovarian cancer. However, more extended studies are encouraged to evaluate the clinical application potential of these lncRNAs in the prognosis evaluation of ovarian cancer.

Combination of NDRG2 overexpression, X-ray radiation and docetaxel enhances apoptosis and inhibits invasiveness properties of LNCaP cells.

OBJECTIVE: N-myc downstream regulated gene 2 (NDRG2) is identified as a promising candidate tumor suppressor in several human malignancies including prostate cancer (PCa). Here, we investigated the effect of combined NDRG2 overexpression, x-ray radiation (RTX), and docetaxel (DTX) against viability and invasiveness properties of LNCaP cells. MATERIAL AND METHODS: A plasmid harboring NDRG2 gene under transcriptional control of prostate-specific enhancing sequence regulatory element was constructed to overexpress NDRG2 in PCa cell lines. The effects of NDRG2 overexpression in combination with RTX and DTX on viability, proliferation, and apoptosis of LNCaP cells were evaluated using MTT, colony formation, and annexin V flowcytometirc assays. Migration and invasion of NDRG2-overexpressed cells as well as expression of matrix metalloproteinses-2 (MMP2) and -9 (MMP9) were also assessed using transwell chamber assay and real-time PCR. RESULTS: The results of fluorescence microscopy and real-time PCR showed a high and specific overexpression of NDRG2 in LNCaP cells. Overexpression of NDRG2 significantly reduced cell viability and increased apoptosis of LNCaP cell. Migration, invasion, as well as the expression of MMP2 and MMP9, was decreased following NDRG2 overexpression. Combination of NDRG2 overexpression with RTX and DTX decreased the viability, invasion, and migration of LNCaP cells synergistically. CONCLUSION: These results indicate that a combination of NDRG2 overexpression with chemotherapy and radiotherapy can be considered for effective treatment of PCa.

NDRG2 Regulates the Expression of Genes Involved in Epithelial Mesenchymal Transition of Prostate Cancer Cells.

BACKGROUND: Metastasis is the main cause of prostate cancer (PCa) death. The inhibitory effect of N-myc downstream-regulated gene 2 (NDRG2) on the invasiveness properties of PCa cells has been demonstrated previously. However, its underlying mechanisms have not yet been investigated. The present study aimed to investigate the effects of NDRG2 overexpression on the expression of genes involved in epithelial-mesenchymal transition (EMT) including E-cadherin (E-CAD), α- and ß-catenins, Slug and Snail, transforming growth factor (TGF)-α and -ß, and vascular endothelial growth factor (VEGF). METHODS: In the present in vitro study, LNCaP cells were divided into three groups, namely NDRG2 group (transfected with PSES-pAdenoVator-PSA-NDRG2-IRES-GFP plasmid), mock group (transfected with mock plasmid), and control group (without transfection). The effect of NDRG2 overexpression on the migration and invasion of LNCaP cells were investigated using the transwell assay. Real-time PCR was used for the evaluation of gene expression. For the statistical analyses, one-way ANOVA, student t test or Mann-Whitney U test were applied using the SPSS software (version 15.0). P values <0.05 were considered statistically significant. RESULTS: The results demonstrated that the overexpression of NDRG2 reduced the invasion and migration of LNCaP cells compared to the control and mock groups (P<0.001). A decreased expression of TGF-ß (P=0.002), VEGF (P=0.014), Slug (P=0.005), and Snail (P=0.012); and an increased expression of E-CAD (P=0.009) were observed following NDRG2 overexpression in LNCaP cells. CONCLUSION: The results of the present study suggest that NDRG2 inhibits the invasiveness properties of LNCaP cells probably through changes in the expression of genes involved in EMT.

Studies on combination of oxaliplatin and dendrosomal nanocurcumin on proliferation, apoptosis induction, and long non-coding RNA expression in ovarian cancer cells.

Drug resistance remains a major challenge in the treatment of patients with ovarian cancer. Therefore, the development of new anticancer drugs is a clinical priority to develop more effective therapies. New approaches to improve clinical outcomes and limit the toxicity of anticancer drugs focus on chemoprevention. The aim of this study was to determine the effects of dendrosomal nanocurcumin (DNC) and oxaliplatin (Oxa) and their combination on cell death and apoptosis induction in human ovarian carcinoma cell lines analyzed by MTT assay and flow cytometry, respectively. The synergism effect of Oxa and DNC was analyzed using the equation derived from Chou and Talalay. In addition, real-time PCR was used to measure the effect of this combination on the expression levels of long non-coding RNAs with different expression in ovarian cancer and normal ovaries. Our data showed that the effect of DNC on cell death is more than curcumin alone in the same concentration. The greatest cell death effect was observed in combination of Oxa with DNC, while Oxa was added first, followed by DNC at 4 h interval (0/4 h). The findings indicated that DNC induced apoptosis significantly in both cell lines as compared to control groups; however, combination of both agents had no significant effect in apoptosis induction. In addition, combination of both agents significantly affects the relative expression of long non-coding RNAs investigated in the study as compared with mono therapy.