No abstract

Background: Prostate cancer (Pca) is a heterogeneous disease, and current treatments are not based on molecular stratification. Poly(adenosine diphosphate [ADP]-ribose) polymerase (PARP) inhibitors have recently been found to be remarkably toxic to cells with defects in homologous recombination, particularly cells with BRCA-mutated backgrounds. Therefore, this preliminary study was designed to evaluate whether PTEN expression status could have an impact on the sensitivity of invasive Pca cells to the PARP inhibitor, AZD2461. Methods: MTT viability test, Annexin V-FITC/propidium iodide double staining, and caspase3 activity assay were used to evaluate the apoptosis and relative expression of PTEN and VEGF in PC-3 and DU145 cell lines using real-time PCR. Results: MTT results showed that the inhibitory effects of AZD2461 were higher in PC-3 than DU145 cells (with IC 50 of 36.48 and 59.03 µM at 48 hours of treatment, respectively). Flow cytometric analysis also showed the same results. When exposed to 40 µM of AZD2461, PC-3 (38.8%) and DU145 (28%) cells underwent apoptosis (p < 0.05). Treatment of cells by AZD2461 also caused a significant increase in apoptosis through caspase3 activation in both cell lines. VEGF mRNA levels in PC-3 cells significantly decreased compared to adjusted untreated cells (p < 0.05) in all measured times while displaying different alteration patterns in DU145 cells (p < 0.05). Conclusion: AZD2461 suppresses the growth of prostate tumor cells since AZD2461 monotherapy could prove to be efficacious, especially against cells not expressing PTEN besides activating the possible apoptosis-independent cell death pathways.

Cancer treatment is challenging due to late-stage diagnosis, drug resistance and systemic toxicity of chemotherapeutic agents. The formulation of the drug into nanoparticles (NPs) can enhance the treatment efficacy and effectiveness. Therefore, a new cationic niosomal formulation, which contains Tween 80, Tween 60, cholesterol and lysine amino acid as a platform model to enhance transfection efficacy and reach more acceptable stability, and curcumin (Cur) as a biological anti-cancer drug, are introduced. Here, the authors focused on the design and synthesis of novel lysine-mediated niosomal NPs for the effectual and controlled release of the antitumor agent, Cur, and turned to optimize niosome formulations, concerning the volume of cholesterol and surfactant to implement these anticancer agents, simultaneously. The characterization of NPs s was carried out and the results showed the successful synthesis of Cur-entrapped niosomal NPs with high efficacy, sufficient positive charges and a favorable size (95/33 nm). The in vitro studies have been performed to investigate the cytotoxicity, cellular uptake and apoptosis of normal and cancer cells treated by black niosome, free Cur and niosom-loaded Cur. The results showed that implementing agents by niosome caused enhanced cytotoxicity, uptake and anticancer activity in cancer cells in comparison with normal cells. Furthermore, the effect of this nanodrug was surveyed on the 4T1 xenografted Balb/C mouse tumor model. Cur delivery to cancer models caused a higher tumor inhibition rate than in other groups.

In this paper, we step forward in optimizing the efficiency of niosomal systems for carrying curcumin and miR-34a as single-/co-delivery to treat breast cancer. Curcumin, via regulation of p53 protein, affects the molecular signaling pathways and leads to cell death. Likewise, miRNAs, via alternation of the expression of genes, can suppress the development of tumor activities. To conquer and optimize the delivery limitation of curcumin and miRNA, niosomal systems with certain compositions (seven formulations) of Tween-80:Tween-60:cholesterol:DOTAP:PEG are introduced, which enhances the carrier size, surface charge, entrapment efficiency, transfection, and drug release. The results showed that Tween-60 has a significant influence on the entrapment efficiency of the composition. By including the PEG and DOTAP, high enhancements in the overall characteristics of the delivery system were observed. To assess the biological activity of samples, with/without the niosomal delivery system, cytotoxicity, apoptosis, in-vitro, and in-vivo cellular uptake were studied. The recorded data revealed better results from niosomal carriers than their free forms. The best result in single delivery was achieved by miRNA in F6, which had the highest apoptosis, uptake, and smallest tumor volumes under a controlled release. In conclusion, we successfully designed a nanoscale niosomal system to carry drugs and genes to the tumor site to treat cancer cells and provided remarkable data for the scientific society.

This research conducted a comparative study on nanoscaled niosomal structures consisting of Tween-80, Tween-60, cholesterol, and dioleoyl-3-trimethylammonium propane (DOTAP). Thin-film hydration technique was used for the preparation and entrapment of curcumin and miRNA in niosomal formulations for enhancing the stability and delivery rate of the agents. Herein, the influence of Tween-80, Tween-60, cholesterol, and DOTAP on the entrapment efficiency (EE%) of curcumin and the physicochemical properties of the carrier are fully discussed. The optimum engineered formulation resulted in a positive charge of +11.23 mV, high EE (100%), smooth surface, spherical shape, small diameter (90 nm), and good stability in physiological buffers. Also, an accelerated cellular uptake, as well as drug release in PBS (pH 7.4, 37°C) after 72 h, were observed. The cytotoxic activity of curcumin (Cur)/miR-34a-loaded nanoparticles was determined by the MTT assay. The results displayed an improved cytotoxic activity of Cur-niosome towards cancer cells compared to free-dispersed Cur. The uptake of Cur-loaded niosome by A280s and A280cp-1 cancer cell lines faced 2.5 folds drop in the concentration compared to its free form. Generally, Cur-niosome exhibits a significant accumulation of superior anti-cancer properties. Likewise, the cytotoxicity of miR-34a-niosome against tumor cells was higher in comparison with its free form. The anti-cancer effects of the gene/drug delivery were investigated in the 4T1 xenografted Balb/C mouse tumor model. According to the in vitro and in vivo results, gene delivery from the modified niosome nanoparticles was distinctly greater than Cur delivery. Therefore, it was concluded that encapsulation of genes in the nano-niosomal delivery system is a promising procedure for the treatment of cancer cells.