Over the years, cyclodextrin uses have been widely reviewed and their proprieties provide a very attractive approach in different biomedical applications. Cyclodextrins, due to their characteristics, are used to transport drugs and have also been studied as molecular chaperones with potential application in protein misfolding diseases. In this study, we designed cyclodextrin polymers containing different contents of β- or γ-cyclodextrin, and a different number of guanidinium positive charges. This allowed exploration of the influence of the charge in delivering a drug and the effect in the protein anti-aggregant ability. The polymers inhibit Amiloid β peptide aggregation; such an ability is modulated by both the type of CyD cavity and the number of charges. We also explored the effect of the new polymers as drug carriers. We tested the Doxorubicin toxicity in different cell lines, A2780, A549, MDA-MB-231 in the presence of the polymers. Data show that the polymers based on γ-cyclodextrin modified the cytotoxicity of doxorubicin in the A2780 cell line.
Abstract
Background: Ovarian cancer (OC) is the 7th most common type of cancer and the 5th cause of cancer-related death among women worldwide. It is a heterogeneous disease which is quite variable from the genomic and histopathological aspect. In addition to the usual treatments for ovarian cancer, its recurrence is quite common, mainly due to lack of complete eradication of cancer stem cells. These cells have different properties such as self-renewal ability and stemness property, including proliferation.Method: In the present study, we isolated cancer stem cells with the CD133 surface marker from the ovarian A2780 cell line and examined the stemness property and self-renewal ability of these cells. Initially, CD133 surface marker expression in this cell line was assessed by the flow cytometry technique. Then, the isolation of these cells was performed by the Magnetic-activated cell sorting (MACS) method. Flow cytometry (FCM) was also used to confirm the isolation efficiency. The levels of mRNA expression were evaluated in several stem cell markers in CD133+ cells compared with CD133- cells. Moreover, the self- renewal ability of the isolated cells was investigated in serum-free culture medium.Results: Ovarian cancer stem cells (OCSCs) with CD133 surface marker showed high expression of some stemness markers such as Sox2, Nanog, Oct4, ABCG2, ALDH1, LGR5 and Msi. These cells also had the ability to regenerate themselves in a serum-free environment.Conclusion: Cancer stem cells can be isolated through surface markers by the MACS technique; they have stemness and self-renewal properties. So, the CD133 surface marker can be introduced as a key CSC marker in the isolation, characterization and targeted therapy of ovarian cancer patients.
Polyether ionophore salinomycin (SAL) and its semi-synthetic derivatives are recognized as very promising anticancer drug candidates due to their activity against various types of cancer cells, including multidrug-resistant populations. Ovarian cancer is the deadliest among gynecologic malignancies, which is connected with the development of chemoresistant forms of the disease in over 70% of patients after initial treatment regimen. Thus, we decided to examine the anticancer properties of SAL and selected SAL derivatives against a series of drug-sensitive (A2780, SK-OV-3) and derived drug-resistant (A2780 CDDP, SK-OV-3 CDDP) ovarian cancer cell lines. Although SAL analogs showed less promising IC50 values than SAL, they were identified as the antitumor agents that significantly overcome the resistance to platinum-based drugs in ovarian cancer, more potent than unmodified SAL and commonly used anticancer drugs—5-fluorouracil, gemcitabine, and cisplatin. Moreover, when compared with SAL used alone, our experiments proved for the first time increased selectivity of SAL-based dual therapy with 5-fluorouracil or gemcitabine, especially towards A2780 cell line. Looking closer at the results, SAL acted synergistically with 5-fluorouracil towards the drug-resistant A2780 cell line. Our results suggest that combinations of SAL with other antineoplastics may become a new therapeutic option for patients with ovarian cancer.
Background: In this study we investigated the function of the non-catalytic region of tyrosine kinase adaptor protein 2 (NCK2) and its correlation with ITGB1 and ITGB4 integrins in driving ovarian cancer (OvCa) aggressiveness. We also evaluated whether NCK2 may influence prognosis in OvCa patients. Methods: Nanofluidic technology was used to analyze expression of NCK2 in 332 OvCa patients. To evaluate mRNA expression of NCK2, integrins and VEGFA in OvCa cell lines, qRT-PCR was performed. Stable NCK2 overexpression was obtained in OVCAR3. qRT-PCR and Western blot were performed to evaluate expression changes of VEGFA, vimentin, ITGB1, ITGB4, MMP2 and MMP9 under normoxia and hypoxia conditions. Coimmunoprecipitation (Co-IP) was performed in the A2780 cell line to study the interaction between NCK2 and proteins of interest. To investigate whether NCK2 can influence anchorage-independent growth, a soft agar assay was completed. Transwell invasion assay was performed on stable-transfected OVCAR-3 cell lines. Results: Nanofluidic data showed NCK2 can play an important role as a factor promoting tumor aggressiveness and survival in OvCa. This role was also linked to the behaviors of ITGB1 and ITGB4. Moreover, in cells overexpressing NCK2, the expression of vimentin, MMP2, MMP9, VEGFA and ITGB1, but not of ITGB4 was induced by hypoxia. Co-IP showed that NCK2 can directly bind ITGB1, but not VEGFA. NCK2 may be involved in mediating cell-extracellular matrix interactions in OvCa cells by influencing tumor aggressiveness. Conclusions: This study provides evidence of a possible role of NCK2 as biomarker of OvCa progression.
A new sesquiterpenoid, 1α,5α-epoxy-4α-hydroxyl-4β,10β-dimethyl-7αH,10αH-guaia-11(13)-en-12-oic acid (1), and four known compounds, lactucin (2), 1β-hydroxy-7αH,8,11βH-eudesm-3-en-8,12-olide (3), 13,14- seco-stigma 9(11),14(15)-dien-3α-ol (4), and bacosterol-3- O-β-D-glucopyranoside (5) were isolated from Cichorium intybus L. Their structures were determined on the basis of detailed analysis of their 1D- and 2D-NMR spectroscopic and mass spectrometric data. Compounds 2 and 4 showed strong activities against the A2780 cell line with IC50 values of 1.81 and 0.07 μM, respectively.
Bioassay guided fractionation of the ethanol extract of a new endemic species of the genus Astrotrichilia led to the isolation of the new antiproliferative 3-(4′-hydroxy-2′,3′-dihydroprenyl)-4,6-dimethoxy-5-methylcoumarin, named astrotricoumarin (8) with an IC50 value of 6.8 μM against the A2780 cell line. The structure of compound 8 was elucidated on the basis of its physical and spectroscopic data, including extensive 1D- and 2D-NMR analysis.
Exploring Charged Polymeric Cyclodextrins for Biomedical Applications