Phase-separated ribosome-nascent chain complexes in genotoxic stress response.

Assemblysomes are EDTA- and RNase-resistant ribonucleoprotein (RNP) complexes of paused ribosomes with protruding nascent polypeptide chains. They have been described in yeast and human cells for the proteasome subunit Rpt1, and the disordered amino-terminal part of the nascent chain was found to be indispensable for the accumulation of the Rpt1-RNP into assemblysomes. Motivated by this, to find other assemblysome-associated RNPs we used bioinformatics to rank subunits of Saccharomyces cerevisiae protein complexes according to their amino-terminal disorder propensity. The results revealed that gene products involved in DNA repair are enriched among the top candidates. The Sgs1 DNA helicase was chosen for experimental validation. We found that indeed nascent chains of Sgs1 form EDTA-resistant RNP condensates, assemblysomes by definition. Moreover, upon exposure to UV, SGS1 mRNA shifted from assemblysomes to polysomes, suggesting that external stimuli are regulators of assemblysome dynamics. We extended our studies to human cell lines. The BLM helicase, ortholog of yeast Sgs1, was identified upon sequencing assemblysome-associated RNAs from the MCF7 human breast cancer cell line, and mRNAs encoding DNA repair proteins were overall enriched. Using the radiation-resistant A549 cell line, we observed by transmission electron microscopy that 1,6-hexanediol, an agent known to disrupt phase-separated condensates, depletes ring ribosome structures compatible with assemblysomes from the cytoplasm of cells and makes the cells more sensitive to X-ray treatment. Taken together, these findings suggest that assemblysomes may be a component of the DNA damage response from yeast to human.

Cancer Therapy by Silver Nanoparticles: Fiction or Reality?

As an emerging new class, metal nanoparticles and especially silver nanoparticles hold great potential in the field of cancer biology. Due to cancer-specific targeting, the consequently attenuated side-effects and the massive anti-cancer features render nanoparticle therapeutics desirable platforms for clinically relevant drug development. In this review, we highlight those characteristics of silver nanoparticle-based therapeutic concepts that are unique, exploitable, and achievable, as well as those that represent the critical hurdle in their advancement to clinical utilization. The collection of findings presented here will describe the features that distinguish silver nanoparticles from other anti-cancer agents and display the realistic opportunities and implications in oncotherapeutic innovations to find out whether cancer therapy by silver nanoparticles is fiction or reality.

Substitutional Diversity-Oriented Synthesis and In Vitro Anticancer Activity of Framework-Integrated Estradiol-Benzisoxazole Chimeras.

Hybridization of steroids and other pharmacophores often modifies the bioactivity of the parent compounds, improving selectivity and side effect profile. In this study, estradiol and 3'-(un)substituted benzisoxazole moieties were combined into novel molecules by structural integration of their aromatic rings. Simple estrogen starting materials, such as estrone, estradiol and estradiol-3-methylether were used for the multistep transformations. Some of the heterocyclic derivatives were prepared from the estrane precursor by a formylation or Friedel-Crafts acylation-oximation-cyclization sequence, whereas others were obtained by a functional group interconversion strategy. The antiproliferative activities of the synthesized compounds were assessed on various human cervical, breast and prostate cancer cell lines (HeLa, MCF-7, PC3, DU-145) and non-cancerous MRC-5 fibroblast cells. Based on the primary cytotoxicity screens, the most effective cancer-selective compounds were selected, their IC50 values were determined and their apoptosis-inducing potential was evaluated by quantitative real-time PCR. Pharmacological studies revealed a strong structure-function relationship, where derivatives with a hydroxyl group on C-17 exhibited stronger anticancer activity compared to the 17-acetylated counterparts. The present study concludes that novel estradiol-benzisoxazole hybrids exert remarkable cancer cell-specific antiproliferative activity and trigger apoptosis in cancer cells.

Estradiol-Based Salicylaldehyde (Thio)Semicarbazones and Their Copper Complexes with Anticancer, Antibacterial and Antioxidant Activities.

A series of novel estradiol-based salicylaldehyde (thio)semicarbazones ((T)SCs) bearing (O,N,S) and (O,N,O) donor sets and their Cu(II) complexes were developed and characterized in detail by 1H and ¹³C nuclear magnetic resonance spectroscopy, UV-visible and electron paramagnetic resonance spectroscopy, electrospray ionization mass spectrometry and elemental analysis. The structure of the Cu(II)-estradiol-semicarbazone complex was revealed by X-ray crystallography. Proton dissociation constants of the ligands and stability constants of the metal complexes were determined in 30% (v/v) DMSO/H2O. Estradiol-(T)SCs form mono-ligand complexes with Cu(II) ions and exhibit high stability with the exception of estradiol-SC. The Cu(II) complexes of estradiol-TSC and its N,N-dimethyl derivative displayed the highest cytotoxicity among the tested compounds in MCF-7, MCF-7 KCR, DU-145, and A549 cancer cells. The complexes do not damage DNA according to both in vitro cell-free and cellular assays. All the Cu(II)-TSC complexes revealed significant activity against the Gram-positive Staphylococcus aureus bacteria strain. Estradiol-TSCs showed efficient antioxidant activity, which was decreased by complexation with Cu(II) ions. The exchange of estrone moiety to estradiol did not result in significant changes to physico-chemical and biological properties.

Polyvinyl-Pyrrolidone-Coated Silver Nanoparticles-The Colloidal, Chemical, and Biological Consequences of Steric Stabilization under Biorelevant Conditions.

(1) Background: Several properties of silver nanoparticles (AgNPs), such as cytotoxic, anticancer, and antimicrobial activities, have been subjects of intense research; however, important aspects such as nanoparticle aggregation are generally neglected, although a decline in colloidal stability leads to a loss of the desired biological activities. Colloidal stability is affected by pH, ionic strength, or a plethora of biomolecules that interact with AgNPs under biorelevant conditions. (2) Methods: As only a few studies have focused on the relationship between aggregation behavior and the biological properties of AgNPs, here, we have systematically evaluated this issue by completing a thorough analysis of sterically (via polyvinyl-pyrrolidone (PVP)) stabilized AgNPs that were subjected to different circumstances. We assessed ultraviolet-visible light absorption, dynamic light scattering, zeta potential measurements, in vitro cell viability, and microdilution assays to screen both colloidal stability as well as bioactivity. (3) Results: The results revealed that although PVP provided outstanding biorelevant colloidal stability, the chemical stability of AgNPs could not be maintained completely with this capping material. (4) Conclusion: These unexpected findings led to the realization that stabilizing materials have more profound importance in association with biorelevant applications of nanomaterials than just being simple colloidal stabilizers.

Green Silver and Gold Nanoparticles: Biological Synthesis Approaches and Potentials for Biomedical Applications.

The nanomaterial industry generates gigantic quantities of metal-based nanomaterials for various technological and biomedical applications; however, concomitantly, it places a massive burden on the environment by utilizing toxic chemicals for the production process and leaving hazardous waste materials behind. Moreover, the employed, often unpleasant chemicals can affect the biocompatibility of the generated particles and severely restrict their application possibilities. On these grounds, green synthetic approaches have emerged, offering eco-friendly, sustainable, nature-derived alternative production methods, thus attenuating the ecological footprint of the nanomaterial industry. In the last decade, a plethora of biological materials has been tested to probe their suitability for nanomaterial synthesis. Although most of these approaches were successful, a large body of evidence indicates that the green material or entity used for the production would substantially define the physical and chemical properties and as a consequence, the biological activities of the obtained nanomaterials. The present review provides a comprehensive collection of the most recent green methodologies, surveys the major nanoparticle characterization techniques and screens the effects triggered by the obtained nanomaterials in various living systems to give an impression on the biomedical potential of green synthesized silver and gold nanoparticles.

Size-dependent activity of silver nanoparticles on the morphological switch and biofilm formation of opportunistic pathogenic yeasts.

BACKGROUND: Dimorphism and biofilm formation are important virulence factors of some opportunistic human pathogenic yeasts. Such species commensally colonize skin or mucosal surfaces generally in yeast form, but under particular circumstances, convert into virulent hyphae and disseminate internal organs or cause mucocutaneous infections. The yeast-to-hypha shape-conversion promotes the development of a biofilm, a thick extracellular matrix with sessile cells within. The biofilm is capable to prevent the penetration of antifungal drugs, rendering the surviving biofilm-resident cells intrinsic sources of recurrent infections. The aim of this study was to evaluate the ability of silver nanoparticles (AgNPs) to attenuate the morphological switch and biofilm formation of several opportunistic pathogenic yeasts and to determine whether this feature depends on the nanoparticle size. RESULTS: AgNPs in three different sizes were prepared by chemical reduction approach and characterized by transmission electron microscopy, ultraviolet-visible spectroscopy and dynamic light scattering. The antifungal activity was evaluated by the microdilution method, the inhibitory capacity on biofilm formation and the biofilm degradation ability of differently sized AgNPs was assessed by viability assay. The morphological state of opportunistic pathogenic yeast cells in monoculture and in co-culture with human keratinocytes in the presence of AgNPs was examined by flow cytometry and scanning electron microscopy. All the three AgNPs inhibited the growth of the examined opportunistic pathogenic yeasts, nevertheless, AgNPs with the smallest diameter exhibited the most prominent toxic activities. AgNPs attenuated the biofilm formation in a nanoparticle size-dependent manner; however, their biofilm destruction capacity was negligible. AgNPs with the smallest size exerted the most significant effect on suppressing the morphological change of pathogens in monoculture as well as in a co-culture with keratinocytes. CONCLUSIONS: Our results confirm that AgNPs are capable to hinder yeast-to-hypha morphological conversion and biofilm formation of opportunistic pathogens and this biological effect of AgNPs is size-dependent.

Core-shell nanoparticles suppress metastasis and modify the tumour-supportive activity of cancer-associated fibroblasts.

BACKGROUND: Although accumulating evidence suggests that the crosstalk between malignant cells and cancer-associated fibroblasts (CAFs) actively contributes to tumour growth and metastatic dissemination, therapeutic strategies targeting tumour stroma are still not common in the clinical practice. Metal-based nanomaterials have been shown to exert excellent cytotoxic and anti-cancerous activities, however, their effects on the reactive stroma have never been investigated in details. Thus, using feasible in vitro and in vivo systems to model tumour microenvironment, we tested whether the presence of gold, silver or gold-core silver-shell nanoparticles exerts anti-tumour and metastasis suppressing activities by influencing the tumour-supporting activity of stromal fibroblasts. RESULTS: We found that the presence of gold-core silver-shell hybrid nanomaterials in the tumour microenvironment attenuated the tumour cell-promoting behaviour of CAFs, and this phenomenon led to a prominent attenuation of metastatic dissemination in vivo as well. Mechanistically, transcriptome analysis on tumour-promoting CAFs revealed that silver-based nanomaterials trigger expressional changes in genes related to cancer invasion and tumour metastasis. CONCLUSIONS: Here we report that metal nanoparticles can influence the cancer-promoting activity of tumour stroma by affecting the gene expressional and secretory profiles of stromal fibroblasts and thereby altering their intrinsic crosstalk with malignant cells. This potential of metal nanomaterials should be exploited in multimodal treatment approaches and translated into improved therapeutic outcomes.

Multistep Synthesis and In Vitro Anticancer Evaluation of 2-Pyrazolyl-Estradiol Derivatives, Pyrazolocoumarin-Estradiol Hybrids and Analogous Compounds.

Although the hormone independent cytotoxic activity of several estradiol derivatives endowed with a simple substituent at C-2 has been reported so far, 2-heterocyclic and 2,3-condensed analogs are less investigated from both synthetic and pharmacological points of view. Therefore, novel A-ring-connected 2-pyrazoles of estradiol and, for comparison, their structurally simplified non-steroidal pairs were synthesized from estradiol 3-methyl ether and 6-methoxy-1,2,3,4-tetrahydronaphthalene. Friedel-Crafts acetylation of the protected phenolic compounds and subsequent O-demethylation led to ortho-substituted derivatives regioselectively, which were converted to arylhydrazones with phenylhydrazine, 4-tolylhydrazine and 4-chloro-phenylhydrazine, respectively, under microwave conditions. The hydrazones were subjected to cyclization with the Vilsmeier-Haack reagent immediately after preparation and the ring closure/formylation sequence resulted in steroidal and non-steroidal 4'-formylpyrazoles in moderate to good yields. During reductive transformations, 4-hydroxymethyl-pyrazoles were obtained, while oxidative lactonization of the 4-formylpyrazole moiety with the phenolic OH in the presence of the Jones reagent afforded A-ring-integrated pyrazolocoumarin hybrids and related analogs. Steroidal pyrazoles, which were produced as C-17 acetates due to acetylation of C-17 OH during the primary Friedel-Crafts reaction, underwent deacetylation in alkaline methanol to furnish 2-heterocyclic estradiol derivatives. Pharmacological studies revealed the overall and cancer cell-specific cytotoxicity of the derivatives and the half maximal inhibitory concentrations were obtained for the most promising compounds.

Endoplasmic reticulum stress: major player in size-dependent inhibition of P-glycoprotein by silver nanoparticles in multidrug-resistant breast cancer cells.

BACKGROUND: Development of multidrug resistance (MDR) is a major burden of successful chemotherapy, therefore, novel approaches to defeat MDR are imperative. Although the remarkable anti-cancer propensity of silver nanoparticles (AgNP) has been demonstrated and their potential application in MDR cancer has been proposed, the nanoparticle size-dependent cellular events directing P-glycoprotein (Pgp) expression and activity in MDR cancer have never been addressed. Hence, in the present study we examined AgNP size-dependent cellular features in multidrug resistant breast cancer cells. RESULTS: In this study we report that 75 nm AgNPs inhibited significantly Pgp efflux activity in drug-resistant breast cancer cells and potentiated the apoptotic effect of doxorubicin, which features were not observed upon 5 nm AgNP treatment. Although both sized AgNPs induced significant ROS production and mitochondrial damage, 5 nm AgNPs were more potent than 75 nm AgNPs in this respect, therefore, these effects can not to be accounted for the reduced transport activity of ATP-driven pumps observed after 75 nm AgNP treatments. Instead we found that 75 nm AgNPs depleted endoplasmic reticulum (ER) calcium stores, caused notable ER stress and decreased plasma membrane positioning of Pgp. CONCLUSION: Our study suggests that AgNPs are potent inhibitors of Pgp function and are promising agents for sensitizing multidrug resistant breast cancers to anticancer drugs. This potency is determined by their size, since 75 nm AgNPs are more efficient than smaller counterparts. This is a highly relevant finding as it renders AgNPs attractive candidates in rational design of therapeutically useful agents for tumor targeting. In the present study we provide evidence that exploitation of ER stress can be a propitious target in defeating multidrug resistance in cancers.

Anti-Cancer Activity of Novel Dihydrotestosterone-Derived Ring A-Condensed Pyrazoles on Androgen Non-Responsive Prostate Cancer Cell Lines.

Regioselective synthesis of novel ring A-fused arylpyrazoles of dihydrotestosterone (DHT) was carried out in two steps under facile reaction conditions. Aldol condensation of DHT with acetaldehyde afforded a 2-ethylidene derivative regio- and stereo-selectively, which was reacted with different arylhydrazines in the presence of iodine via microwave-assisted oxidative cyclization reactions. The 17-keto analogs of steroidal pyrazoles were also synthesized by simple oxidation in order to enlarge the compound library available for pharmacological studies and to obtain structure-activity relationship. The antiproliferative activities of the structurally related heteroaromatic compounds were tested in vitro on human cervical and breast adenocarcinoma cell lines (HeLa, MCF-7 and MDA-MB-231) and on two androgen-independent malignant prostate carcinoma cell lines (PC-3 and DU 145). Based on primary cytotoxicity screens and IC50 assessment, a structure-function relationship was identified, as derivatives carrying a hydroxyl group on C-17 exhibit stronger activity compared to the 17-one counterparts. Cancer cell selectivity of the derivatives was also determined using non-cancerous MRC-5 cells. Furthermore, the proapoptotic effects of some selected derivatives were verified on androgen therapy refractive p53-deficient PC-3 cells. The present study concludes that novel DHT-derived arylpyrazoles exert cancer cell specific antiproliferative activity and activate apoptosis in PC-3 cells.

The cytoprotective effect of biglycan core protein involves Toll-like receptor 4 signaling in cardiomyocytes.

AIMS: Exogenously administered biglycan (core protein with high-molecular weight glycosaminoglycan chains) has been shown to protect neonatal cardiomyocytes against simulated ischemia/reperfusion injury (SI/R), however, the mechanism of action is not clear. In this study we aimed to investigate, which structural component of biglycan is responsible for its cardiocytoprotective effect and to further explore the molecular mechanisms involved in the cytoprotection. METHODS AND RESULTS: A pilot study was conducted to demonstrate that both native (glycanated) and deglycanated biglycan can attenuate cell death induced by SI/R in a dose-dependent manner in primary neonatal cardiomyocytes isolated from Wistar rats. In separate experiments, we have shown that similarly to glycanated biglycan, recombinant human biglycan core protein (rhBGNc) protects cardiomyocytes against SI/R injury. In contrast, the glycosaminoglycan component dermatan sulfate had no significant effect on cell viability, while chondroitin sulfate further enhanced cell death induced by SI/R. Treatment of cardiomyocytes with rhBGNc reverses the effect of SI/R upon markers of necrosis, apoptosis, mitochondrial membrane potential, and autophagy. We have also shown that pharmacological blockade of Toll-like receptor 4 (TLR4) signaling or its downstream mediators (IRAK1/4, ERK, JNK and p38 MAP kinases) abolished the cytoprotective effect of rhBGNc against SI/R injury. Pretreatment of cardiomyocytes with rhBGNc for 20h resulted in increased Akt phosphorylation and NO production without having significant effect on phosphorylation of ERK1/2, STAT3, and on the production of superoxide. Treatment over 10min and 1h with rhBGNc increased ERK1 phosphorylation, while the SI/R-induced increase in superoxide production was attenuated by rhBGNc. Blockade of NO synthesis also prevented the cardiocytoprotective effect of rhBGNc. CONCLUSIONS: The core protein of exogenous biglycan protects myocardial cells from SI/R injury via TLR4-mediated mechanisms involving activation of ERK, JNK and p38 MAP kinases and increased NO production. The cytoprotective effect of rhBGNc is due to modulation of SI/R-induced changes in necrosis, apoptosis and autophagy.

Extracellular deposition of matrilin-2 controls the timing of the myogenic program during muscle regeneration.

Here, we identify a role for the matrilin-2 (Matn2) extracellular matrix protein in controlling the early stages of myogenic differentiation. We observed Matn2 deposition around proliferating, differentiating and fusing myoblasts in culture and during muscle regeneration in vivo. Silencing of Matn2 delayed the expression of the Cdk inhibitor p21 and of the myogenic genes Nfix, MyoD and Myog, explaining the retarded cell cycle exit and myoblast differentiation. Rescue of Matn2 expression restored differentiation and the expression of p21 and of the myogenic genes. TGF-ß1 inhibited myogenic differentiation at least in part by repressing Matn2 expression, which inhibited the onset of a positive-feedback loop whereby Matn2 and Nfix activate the expression of one another and activate myoblast differentiation. In vivo, myoblast cell cycle arrest and muscle regeneration was delayed in Matn2(-/-) relative to wild-type mice. The expression levels of Trf3 and myogenic genes were robustly reduced in Matn2(-/-) fetal limbs and in differentiating primary myoblast cultures, establishing Matn2 as a key modulator of the regulatory cascade that initiates terminal myogenic differentiation. Our data thus identify Matn2 as a crucial component of a genetic switch that modulates the onset of tissue repair.

Silver nanoparticles modulate ABC transporter activity and enhance chemotherapy in multidrug resistant cancer.

The emergence of multidrug resistant (MDR) cancer phenotypes dramatically attenuates the efficiency of antineoplastic drug treatments often leading to the failure of chemotherapy. Therefore there is an urgent need to engineer new therapeutically useful agents and propose innovative approaches able to defeat resistant cancer cells. Although the remarkable anti-cancer features of silver nanoparticles (AgNPs) have already been delineated their impact on MDR cancer has never been investigated. Herein, we report that AgNPs have notable anti-proliferative effect and induce apoptosis mediated cell death both in drug sensitive and in MDR cancer cells. Furthermore we show evidence that AgNPs exert an inhibitory action on the efflux activity of MDR cancer cells which feature could be exploited to enhance drug accumulation. We verified synergistic interactions of AgNPs with six different antineoplastic agents on drug resistant cells which emphasizes the excellent potential of AgNPs as combinational partners in the chemotherapy of MDR cancer. FROM THE CLINICAL EDITOR: The treatment of cancer often fails due to the development of multidrug resistant (MDR) cancer cells. Hence, novel approaches are being investigated to combat drug resistant cancer cells. One particular method studied here uses silver nanoparticles (AgNPs). The authors showed that AgNPs had anti-proliferative effect and ?exerted an inhibitory action on ABC transporter. The findings could suggest the possible use of AgNPs in combination with other chemotherapeutic agents in the clinical setting.

Ion exchange defines the biological activity of titanate nanotubes.

One-dimensional titanate nanotubes (TiONTs) were subjected to systematic ion exchange to determine the impact of these modifications on biological activities. Ion exchanged TiONTs (with Ag, Mg, Bi, Sb, Ca, K, Sr, Fe, and Cu ions) were successfully synthesized and the presence of the substituted ions was verified by energy dispersive X-ray spectroscopy (EDS). A complex screening was carried out to reveal differences in toxicity to human cells, as well as in antibacterial, antifungal, and antiviral activities between the various modified nanotubes. Our results demonstrated that Ag ion exchanged TiONTs exerted potent antibacterial and antifungal effects against all examined microbial species but were ineffective on viruses. Surprisingly, the antibacterial activity of Cu/TiONTs was restricted to Micrococcus luteus. Most ion exchanged TiONTs did not show antimicrobial activity against the tested bacterial and fungal species. Incorporation of various ions into nanotube architectures lead to mild, moderate, or even to a massive loss of human cell viability; therefore, this type of biological effect exerted by TiONTs can be greatly modulated by ion exchange. These findings further emphasize the contribution of ion exchange in determining not only the physical and chemical characteristics but also the bioactivity of TiONT against different types of living cells.

Multi-round recycling of green waste for the production of iron nanoparticles: synthesis, characterization, and prospects in remediation.

Due to the widespread applications of metal nanoparticles (NPs), green synthesis strategies have recently advanced, e.g., methods that utilize extracts made from different plant wastes. A particularly innovative approach to reducing large amounts of available household/agricultural green wastes is their application in nanoparticle generation. Regarding this, the aim of our work was to examine the possibility of upgrading green nanoparticle syntheses from an innovative economic and environmental point of view, namely by investigating the multiple recyclabilities of green tea (GT), coffee arabica (CA), and Virginia creeper (Parthenocissus quinquefolia) (VC) waste residues for iron nanoparticle (FeNPs) synthesis. The plant extracts obtained by each extraction round were analyzed individually to determine the amount of main components anticipated to be involved in NPs synthesis. The synthesized FeNPs were characterized by X-ray powder diffraction and transmission electron microscopy. The activity of the generated FeNPs in degrading chlorinated volatile organic compounds (VOC) and thus their future applicability for remediation purposes were also assessed. We have found that VC and especially GT residues could be reutilized in multiple extraction rounds; however, only the first extract of CA was suitable for FeNPs' generation. All of the obtained FeNPs could degrade VOC with efficiencies GT1-Fe 91.0%, GT2-Fe 83.2%, GT3-Fe 68.5%; CA1-Fe 76.2%; VC1-Fe 88.2%, VC2-Fe 79.7%, respectively, where the number (as in GT3) marked the extraction round. These results indicate that the adequately selected green waste material can be reutilized in multiple rounds for nanoparticle synthesis, thus offering a clean, sustainable, straightforward alternative to chemical methods.

Semi-Synthetic Dihydrotestosterone Derivatives Modulate Inherent Multidrug Resistance and Sensitize Colon Cancer Cells to Chemotherapy.

Multidrug resistance (MDR) is a serious hurdle to successful cancer therapy. Here, we examined the efficiency of novel semi-synthetic dihydrotestosterone derivatives, more specifically androstano-arylpyrimidines in inhibiting the efflux activity of ATP-binding cassette (ABC) transporters and sensitizing inherently MDR colon cancer cells to various chemotherapy drugs. Using the Rhodamine123 accumulation assay, we evaluated the efflux activity of cancer cells following treatments with androstano-arylpyrimidines. We found that acetylated compounds were capable of attenuating the membrane efflux of inherently MDR cells; however, deacetylated counterparts were ineffective. To delineate the possible molecular mechanisms underlying these unique activities of androstano-arylpyrimidines, the degree of apoptosis induction was assessed by AnnexinV-based assays, both upon the individual as well as by steroid and chemotherapy agent combination treatments. Five dihydrotestosterone derivatives applied in combination with Doxorubicin or Epirubicin triggered massive apoptosis in MDR cells, and these combinations were more efficient than chemotherapy drugs together with Verapamil. Furthermore, our results revealed that androstano-arylpyrimidines induced significant endoplasmic reticulum stress (ER stress) but did not notably modulate ABC transporter expression. Therefore, ER stress triggered by acetylated androstano-arylpyrimidines is probably involved in the mechanism of efflux pump inhibition and drug sensitization which can be targeted in future drug developments to defeat inherently multidrug-resistant cancer.

Medicinal-Chemistry-Driven Approach to 2-Substituted Benzoxazole-Estradiol Chimeras: Synthesis, Anticancer Activity, and Early ADME Profile.

The efficient synthesis of novel estradiol-based A-ring-fused oxazole derivatives, which can be considered as benzoxazole-steroid domain-integrated hybrids containing a common benzene structural motif, is described. The target compounds were prepared from steroidal 2-aminophenol precursors by heterocycle formation or functional group interconversion (FGI) strategies. According to 2D projection-based t-distributed stochastic neighbor embedding (t-SNE), the novel molecules were proved to represent a new chemical space among steroid drugs. They were characterized based on critical physicochemical parameters using in silico and experimental data. The performance of the compounds to inhibit cell proliferation was tested on four human cancer cell lines and non-cancerous cells. Further examinations were performed to reveal IC50 and lipophilic ligand efficiency (LLE) values, cancer cell selectivity, and apoptosis-triggering features. Pharmacological tests and LLE metric revealed that some derivatives, especially the 2-(4-ethylpiperazin-1-yl)oxazole derivative exhibit strong anticancer activity and trigger the apoptosis of cancer cells with relatively low promiscuity risk similarly to the structurally most closely-related and intensively studied anticancer agent, 2-methoxy-estradiol.

Open, prospective, multicenter study on postoperative intranasal phototherapy in nasal polyposis.

BACKGROUND: The therapeutic effect of ultraviolet (UV) light is generally attributed to its immunosuppressive and immunomodulatory effects. Since chronic inflammation is the major factor in the development of nasal polyposis, we have previously used mixed ultraviolet-visible light (mUV-VIS, Rhinolight®) phototherapy for the treatment of nasal polyps. AIMS: In the present open, multicenter study, our aim was to delineate whether mUV-VIS applied postoperatively in vivo together with intranasal steroid treatment could reduce the recurrence of nasal polyps. METHODS: After functional endoscopic sinus surgery, one group of patients received mUV-VIS light together with standard intranasal steroid (mometason furoate 2 × 200 µg) application for a 12-week treatment period, whereas the other patient group obtained only intranasal steroid for the same duration. We recorded nasal endoscopy images and obtained demographical and clinical data, total nasal score (TNS), and nasal obstruction symptom evaluation (NOSE). We performed acoustic rhinometry and measured nasal inspiratory peak flow. Follow-up was 12 months. RESULTS: We found that the recurrence of nasal polyps was significantly diminished, and based on video-endoscopic measurements, the size and grade of recurrent polyps were significantly smaller in the phototherapy-receiving group. Nasal obstruction values and NOSE were significantly better throughout the follow-up period in the mUV-VIS light-treated group than in the intranasal steroid monotreatment group. CONCLUSIONS: Rhinophototherapy together with standard nasal steroid application may have a supportive role in the treatment of recurrent bilateral nasal polyps.

Efficient access to domain-integrated estradiol-flavone hybrids via the corresponding chalcones and their in vitro anticancer potential.

Structural modification of the phenolic A-ring of estrogens at C-2 and/or C-3 significantly reduces or eliminates the hormonal effects of the compounds, thus the incorporation of other pharmacophores into these positions can provide biologically active derivatives suitable for new indications, without possessing unwanted side effects. As part of this work, A-ring integration of estradiol with chalcones and flavones was carried out in the hope of obtaining novel molecular hybrids with anticancer action. The syntheses were performed from 2-acetylestradiol-17ß-acetate which was first reacted with various (hetero)aromatic aldehydes in a pyrrolidine-catalyzed reaction in DMSO. The chalcones thus obtained were then subjected to oxidative cyclization with I2 in DMSO to afford estradiol-flavone hybrids in good yields. All newly synthesized derivatives were tested in vitro for cytotoxicity on human malignant cell lines of diverse origins as well as on a non-cancerous cell line, and the results demonstrated that estradiol-flavone hybrids containing a structure-integrated flavone moiety were the most active and cancer cell-selective agents. The minimal inhibitory concentration values (IC50) were calculated for selected compounds (3c, 3d and 3e) and their apoptosis inducing capacity was verified by RT-qPCR (real-time quantitative polymerase chain reaction). The results suggest an important structure-activity relationship regarding estradiol-flavone hybrids that could form a promising synthetic platform and rationale for future drug developments.