Receptor Activator of NF-κB (RANK) Confers Resistance to Chemotherapy in AML and Associates with Dismal Disease Course

Although treatment options of acute myeloid leukemia (AML) have improved over the recent years, prognosis remains poor. Better understanding of the molecular mechanisms influencing and predicting treatment efficacy may improve disease control and outcome. Here we studied the expression, prognostic relevance and functional role of the tumor necrosis factor receptor (TNFR) family member Receptor Activator of Nuclear Factor (NF)-κB (RANK) in AML. We conducted an experimental ex vivo study using leukemic cells of 54 AML patients. Substantial surface expression of RANK was detected on primary AML cells in 35% of the analyzed patients. We further found that RANK signaling induced the release of cytokines acting as growth and survival factors for the leukemic cells and mediated resistance of AML cells to treatment with doxorubicin and cytarabine, the most commonly used cytostatic compounds in AML treatment. In line, RANK expression correlated with a dismal disease course as revealed by reduced overall survival. Together, our results show that RANK plays a yet unrecognized role in AML pathophysiology and resistance to treatment, and identify RANK as “functional” prognostic marker in AML. Therapeutic modulation of RANK holds promise to improve treatment response in AML patients.

The Dark Side of Platinum Based Cytostatic Drugs: From Detection to Removal

The uncontrolled release of pharmaceutical drugs into the environment raised serious concerns in the last decades as they can potentially exert adverse effects on living organisms even at the low concentrations at which they are typically found. Among them, platinum based cytostatic drugs (Pt CDs) are among the most used drugs in cancer treatments which are administered via intravenous infusion and released partially intact or as transformation products. In this review, the studies on environmental occurrence, transformation, potential ecotoxicity, and possible treatment for the removal of platinum cytostatic compounds are revised. The analysis of the literature highlighted the generally low total platinum concentration values (from a few tens of ng L−1 to a few hundred μg L−1) found in hospital effluents. Additionally, several studies highlighted how hospitals are sources of a minor fraction of the total Pt CDs found in the environment due to the slow excretion rate which is longer than the usual treatment durations. Only some data about the impact of the exposure to low levels of Pt CDs on the health of flora and fauna are present in literature. In some cases, adverse effects have been shown to occur in living organisms, even at low concentrations. Further ecotoxicity data are needed to support or exclude their chronic effects on the ecosystem. Finally, fundamental understanding is required on the platinum drugs removal by MBR, AOPs, technologies, and adsorption.

Multifunctional hybrid nanoplatform based on Fe3O4@Ag NPs for nitric oxide delivery: development, characterization, therapeutic efficacy, and hemocompatibility

The combination of Fe3O4@Ag superparamagnetic hybrid nanoparticles and nitric oxide (NO) represents an innovative strategy for a localized NO delivery with a simultaneous antibacterial and antitumoral actions. Here, we report the design of Fe3O4@Ag hybrid nanoparticles, coated with a modified and nitrosated chitosan polymer, able to release NO in a biological medium. After their synthesis, physicochemical characterization confirmed the obtention of small NO-functionalized superparamagnetic Fe3O4@Ag NPs. Antibacterial assays demonstrated enhanced effects compared to control. Bacteriostatic effect against Gram-positive strains and bactericidal effect against E. coli were demonstrated. Moreover, NO-functionalized Fe3O4@Ag NPs demonstrated improved ability to reduce cancer cells viability and less cytotoxicity against non-tumoral cells compared to Fe3O4@Ag NPs. These effects were associated to the ability of these NPs act simultaneous as cytotoxic (necrosis inductors) and cytostatic compounds inducing S-phase cell cycle arrest. NPs also demonstrated low hemolysis ratio (<10%) at ideal work range, evidencing their potential for biomedical applications.

An Update of the Occurrence of Organic Contaminants of Emerging Concern in the Canary Islands (Spain)

Nowadays, activities associated with industries, cities, and leisure generate a number of different wastes, including many chemical pollutants that enter the environment and negatively affect the wildlife. Some of them are emerging organic contaminants (EOCs), which include UV filters and stabilizers, antineoplastic agents, and natural and synthetic steroid hormones, among others. It is well demonstrated that the presence of this kind of contaminants may produce adverse effects in aquatic environments and also in marine organisms. Even though the Canary Islands (Spain) are one of the most biodiverse parts of the temperature regions of the world, little is known about the presence of these substances in the environment and organisms in the archipelago. For that purpose, the objective of this work was to evaluate the presence of some UV filters, cytostatic compounds, and hormones in water (wastewater and seawater), sediments, and marine organisms. Moreover, we evaluated conventional and natural wastewater treatment plants (WWTPs) to study the removal efficiencies of these target compounds. UV filters and stabilizers were found in all the analysed samples and were the only target family found in seawater (with UV-329 appearing at all the locations at concentrations between 67.5 and 859 ng L−1). Some cytostatic compounds were detected in hospital wastewater at concentrations between 375.8 and 1851 ng L−1, but not in the analysis of sludge or fish samples. Hormones were detected in wastewater, sludge, and fish samples, and their removal in the natural treatment system (over 76% for all the hormones) allowed to prove it as an efficient technology for the elimination of these EOCs from urban wastewaters in small communities.

Screening of cytotoxic or cytostatic flavonoids with quantitative Fluorescent Ubiquitination-based Cell Cycle Indicator-based cell cycle assay

The Fluorescent Ubiquitination-based Cell Cycle Indicator (FUCCI) system can be used not only to study gene expression at a specific cell cycle stage, but also to monitor cell cycle transitions in real time. In this study, we used a single clone of FUCCI-expressing HeLa cells (FUCCI-HeLa cells) and monitored the cell cycle in individual live cells over time by determining the ratios between red fluorescence (RF) of RFP-Cdt1 and green fluorescence (GF) of GFP-Geminin. Cytotoxic and cytostatic compounds, the latter of which induced G2 or mitotic arrest, were identified based on periodic cycling of the RF/GF and GF/RF ratios in FUCCI-HeLa cells treated with anti-cancer drugs. With this cell cycle monitoring system, ten flavonoids were screened. Of these, apigenin and luteolin, which have a flavone backbone, were cytotoxic, whereas kaempferol, which has a flavonol backbone, was cytostatic and induced G2 arrest. In summary, we developed a system to quantitatively monitor the cell cycle in real time. This system can be used to identify novel compounds that modulate the cell cycle and to investigate structure–activity relationships.