2-(Methyl(phenyl)amino)-N-(phenyloxyphenyl)acetamide structural motif representing a framework for selective SIRT2 inhibition.

The mammalian cytoplasmic protein SIRT2, a class III histone deacetylase family member, possesses NAD+-dependent lysine deacetylase/deacylase activity. Dysregulation of SIRT2 has been implicated in the pathogenesis of several diseases, including neurological and metabolic disorders and cancer; thus, SIRT2 emerges as a potential therapeutic target. Herein, we identified a series of diaryl acetamides (ST61-ST90) by the structural optimization of our hit STH2, followed by enhanced SIRT2 inhibitory potency and selectivity. Among them, ST72, ST85, and ST88 selectively inhibited SIRT2 with IC50 values of 9.97, 5.74, and 8.92 µM, respectively. Finally, the entire study was accompanied by in silico prediction of binding modes of docked compounds and the stability of SIRT2-ligand complexes. We hope our findings will provide substantial information for designing selective inhibitors of SIRT2.

Role of parental smoking and environmental tobacco smoke exposure in childhood cancer: A study using hair cotinine analysis and questionnaires.

OBJECTIVES: In the etiology of childhood cancers, many genetic and environmental factors play a role. One of these factors could be cigarette smoking, and the main source of tobacco smoke exposure of children is parental smoking. However, establishing a causal relationship between parental smoking and childhood cancers has proven challenging due to difficulties in accurately detecting tobacco smoke exposure METHODS: To address this issue, we used hair cotinine analysis and a questionnaire to get information about tobacco smoke exposures of pediatric cancer patients and healthy children. A total of 104 pediatric cancer patients and 99 healthy children participated in our study. Parental smoking behaviors (pre-conceptional, during pregnancy, and current smoking) and environmental tobacco smoke (ETS) exposures of children are compared. RESULTS: We have found no differences between two groups by means of maternal smoking behaviors. However, the rates of paternal pre-conceptional smoking and smoking during pregnancy were significantly low in cancer patients (p < .05). These data suggest that social desirability bias among fathers of cancer patients may have contributed to this discrepancy. According to questionnaire, cancer patients had significantly lower ETS exposures than healthy children (p < .05). However, ETS exposure assessment through cotinine analysis demonstrated that cancer patients had higher exposure to ETS compared to healthy children (p < .001). CONCLUSION: Our findings provide evidence supporting the potential role of smoking as a risk factor for childhood cancers. This study also revealed that questionnaires could cause biases. We suggest that cotinine analysis along with validated questionnaires can be used to prevent biases in studies of tobacco smoke in the etiology of childhood cancers.

In silico approach reveals N-(5-phenoxythiophen-2-yl)-2-(arylthio)acetamides as promising selective SIRT2 inhibitors: the case of structural optimization of virtual screening-derived hits.

Epigenetic modifications play an essential role in tumor suppression and promotion. Among the diverse range of epigenetic regulators, SIRT2, a member of NAD+-dependent protein deacetylates, has emerged as a crucial regulator of cellular processes, including cell cycle progression, DNA repair, and metabolism, impacting tumor growth and survival. In the present work, a series of N-(5-phenoxythiophen-2-yl)-2-(arylthio)acetamide derivatives were identified following a structural optimization of previously reported virtual screening hits, accompanied by enhanced SIRT2 inhibitory potency. Among the compounds, ST44 and ST45 selectively inhibited SIRT2 with IC50 values of 6.50 and 7.24 µM, respectively. The predicted binding modes of the two compounds revealed the success of the optimization run. Moreover, ST44 displayed antiproliferative effects on the MCF-7 human breast cancer cell line. Further, the contribution of SIRT2 inhibition in this effect of ST44 was supported by western blotting, affording an increased α-tubulin acetylation. Furthermore, molecular dynamics (MD) simulations and binding free energy calculations using molecular mechanics/generalized born surface area (MM-GBSA) method evaluated the accuracy of predicted binding poses and ligand affinities. The results revealed that ST44 exhibited a remarkable level of stability, with minimal deviations from its initial docking conformation. These findings represented a significant improvement over the virtual screening hits and may contribute substantially to our knowledge for further selective SIRT2 drug discovery.Communicated by Ramaswamy H. Sarma.

Effects of pyrrolopyrimidine derivatives on cancer cells cultured in vitro and potential mechanism.

In this study, the anticancer activities of some pyrrolopyrimidine derivatives were evaluated. Compound 3 is the most cytotoxic compound on MCF-7 cancer cells with an IC50 value of 23.42 µM. Also, compound 3 induced apoptosis and the ROS(+) cell population in MCF-7 cells. Moreover, it significantly reduced MMP-9 activity, having 42.16 ± 5.10% and 58.28 ± 1.96% inhibitory activities at 10 µM and 50 µM concentrations, respectively. Molecular docking results supported the activity, showing key hydrogen bonds with the binding site of MMP-9. Therefore, compound 3 might be a lead compound for the development of potent MMP-9 inhibitors.

Cuproptosis as the new kryptonite of cancer: a copper-dependent novel cell death mechanism with promising implications for the treatment of hepatocellular carcinoma.

Copper is an essential element for critical cellular functions such as mitochondrial respiration, cholesterol biosynthesis and immune response. Altered copper homeostasis has been associated with various disorders, including cancer. The copper overload is known to contribute to tumorigenesis, angiogenesis and metastasis, and recently it has been suggested that the elevated level of this element may also create vulnerability to a novel cell death mechanism, named cuproptosis. Excessive amount of copper in mitochondria binds to lipoylated enzymes of the TCA cycle and forms insoluble oligomers. The aggregation of these oligomers and subsequent iron-sulfur cluster protein loss results in proteotoxic stress and eventual cell death. Hepatocellular carcinoma is a common malignancy with a low survival rate, despite the available treatment options. The discovery of cuproptosis led many researchers to explore its potential use in hepatocellular cancer therapy due to the rich mitochondria content of hepatic cells. In this regard, a number of genomic studies were conducted to discover several cuproptosis-related genes and explored their association with prognosis, survival and immunotherapy response. This review brings together the available data on the relationship between cuproptosis and hepatocellular cancer for the first time, and highlights some of the potential biomarkers or target molecules that may be useful in the treatment.

Alpha-lipoic acid induced apoptosis of PC3 prostate cancer cells through an alteration on mitochondrial membrane depolarization and MMP-9 mRNA expression.

Cancer has become an important cause of mortality and morbidity in the world. Over the past decades, biomedical research revealed insights into the molecular events and signaling pathways involved in carcinogenesis and cancer progression. Matrix metalloproteinases (MMPs) are a diverse family of enzymes that can degrade various components of the extracellular matrix and are considered as potential diagnostic and prognostic biomarkers for many cancer types and cancer stages. Recently, studies on the role of natural-origin active substances in the prevention of cancer development gained importance. Among them, the α-lipoic acid, which is commonly found in plants, displayed potent anti-proliferative effects on cancer cell lines. However, the effect of the compound on the induction of apoptosis and mRNA expression of MMPs in human prostate cancer cells remains unclear. The present study aimed to evaluate the anti-proliferative and apoptotic activity of α-lipoic acid in human PC3 prostate carcinoma cells considering different concentrations and exposure durations. The findings showed that, α-lipoic acid significantly decreased PC3 cell viability with an IC50 value of 1.71 mM at 48 h (p < 0.05). Additionally, the compound significantly increased Annexin-V binding in cells compared to control and induced a significant alteration in mitochondrial membrane potential and caspase levels (p < 0.05). Furhermore, the RT-PCR analyses have revealed that α-lipoic acid reduced MMP-9 mRNA expression in PC3 cells compared to the control (p < 0.05). In conclusion, this study highlights that α-lipoic acid induced apoptosis in human PC3 prostate cancer cells and inhibited the MMP-9 gene at the mRNA level, which is known to play a role in metastasis development.

The five Ferulago species inhibited cell proliferation and induced apoptosis of A549, MCF-7, PC3 and SW480 cancer cells in vitro.

In this study, it was aimed to evaluate the cytotoxic and apoptotic activities of ethanolic extracts prepared from the roots of 5 Ferulago species [F. humilis Boiss., F. macrosciadia Boiss. & Balansa, F. sandrasica Pesmen & Quézel, F. silaifolia (Boiss.) Boiss., F. trojana Akalin & Pimenov] on various human cancer cell lines. The cytotoxicity analyses against human lung (A549), breast (MCF-7), prostate (PC3) and colon (SW480) cancer cell lines were determined by MTT test; while the apoptotic effect was evaluated by Annexin V binding assay. All studied extracts showed concentration-dependent cytotoxic activity with an IC50 value ranging from 0.416 to 5.336 mg/mL. The studied Ferulago species significantly induced apoptosis of cancer cells, while F. macrosciadia had the highest apoptotic activity on MCF-7 cells with 21.79 ± 1.63% apoptotic cell population (p < 0.0001). In addition, felamedin and prantschimgin content of the extracts, which are common coumarins in Ferulago species, were evaluated by HPLC. According to HPLC analysis, the highest amount of felamedin content was found in F. trojana, while the highest content of prantschimgin was found in F. sandrasica among the studied Ferulago species. This preliminary research has revealed that the studied Ferulago species have promising effects on various cancer cell lines. Further studies are planned to determine the compounds responsible for the effect and underlying mechanism.

Mitochondrial transplantation: Effects on chemotherapy in prostate and ovarian cancer cells in vitro and in vivo.

Prostate and ovarian cancers affect the male and female reproductive organs and are among the most common cancers in developing countries. Previous studies have demonstrated that cancer cells have a high rate of aerobic glycolysis that is present in nearly all invasive human cancers and persists even under normoxic conditions. Aerobic glycolysis has been correlated with chemotherapeutic resistance and tumor aggressiveness. These data suggest that mitochondrial dysfunction may confer a significant proliferative advantage during the somatic evolution of cancer. In this study we investigated the effect of direct mitochondria transplantation on cancer cell proliferation and chemotherapeutic sensitivity in prostate and ovarian cancer models, both in vitro and in vivo. Our results show that the transplantation of viable, respiration competent mitochondria has no effect on cancer cell proliferation but significantly decreases migration and alters cell cycle checkpoints. Our results further demonstrate that mitochondrial transplantation significantly increases chemotherapeutic sensitivity, providing similar apoptotic levels with low-dose chemotherapy as that achieved with high-dose chemotherapy. These results suggest that mitochondria transplantation provides a novel approach for early prostate and ovarian cancer therapy, significantly increasing chemotherapeutic sensitivity in in vitro and in vivo murine models.

Etoposide in combination with erastin synergistically altered iron homeostasis and induced ferroptotic cell death through regulating IREB2/FPN1 expression in estrogen receptor positive-breast cancer cells.

AIM: Ferroptosis is an iron-dependent cell death mechanism that substantially differs from apoptosis. Since its mechanism involves increased oxidative stress and rich iron content, cancer cells are particularly vulnerable to ferroptotic death compared to healthy tissues. In the present study, the effect of etoposide in combination with a ferroptotic agent, erastin, was investigated in breast cancer. MAIN METHODS: Cell viability was assessed by the MTT assay. Oxidative stress, lipid peroxidation and glutathione peroxidase activity were detected using the relevant kits. Intracellular iron levels were measured by HPLC. Ferroptosis markers were explored by western blotting. KEY FINDINGS: Results demonstrated that although etoposide didn't induce a significant cell death up to 50 µM in MCF-7 cells, with the addition of erastin, a significant synergistic activity was achieved at a dose as low as 1 µM (p < 0.05), contrary to normal breast epithelial cells. This cytotoxic effect was blocked by ferrostatin-1, which is a specific inhibitor of ferroptosis. The combined treatment of etoposide and erastin synergistically induced oxidative stress and lipid peroxidation, while suppressing glutathione peroxidase activity. More importantly, the combination treatment synergistically increased iron accumulation, which was associated with altered expression of IREB2/FPN1. Additionally, ferroptosis-regulating proteins ACSF2 and GPX4 were altered more potently by the combination treatment, compared to untreated cells and erastin treatment alone (p < 0.05). SIGNIFICANCE: In conclusion, this is the first study that reports enhanced cytotoxicity of etoposide, in combination with erastin, in ER-positive breast cancer cells via activation of ferroptotic pathways, and offers a new perspective for future regimens.

Investigation on formulation parameters of donepezil HCl loaded solid lipid nanoparticles

Abstract Donepezil-HCl is a member of the acetylcholinesterase inhibitors that is indicated for the symptomatic treatment of Alzheimer's disease (AD) and has many side effects. In this study, to reduce the side effects of Donepezil-HCl and increase the penetration of the drug through the blood-brain barrier, we aimed to design a solid lipid nanoparticle (SLN) formulation. The effects of the different formulation parameters, such as homogenization speed, sonication time, lipid and drug concentration, surfactant type and concentration, and volume of the aqueous phase, were assessed for optimization. The particle size and PDI increased with increasing lipid concentration but decreased with increasing amounts of surfactant (Tween 80) and co-surfactant (lecithin). When the homogenization rate and sonication time increased, the particle size decreased and the encapsulation efficiency increased. The optimized formulation exhibited particle size, PDI, encapsulation efficiency, and zeta potential of 87.2±0.11 nm; 0.22±0.02; 93.84±0.01 %; -17.0±0.12 mV respectively. The in vitro release investigation revealed that approximately 70% of Donepezil-HCl was cumulatively released after 24 hours. TEM analysis proved that spherical and smooth particles were obtained and formulations had no toxic effect on cells. The final optimized formulation could be a candidate for Donepezil-HCl application in Alzheimer's treatment with reduced side effects and doses for patients

Atorvastatin induces downregulation of matrix metalloproteinase-2/9 in MDA-MB-231 triple negative breast cancer cells.

Matrix metalloproteinases (MMPs) are a family of endopeptidases, mainly responsible of extracellular tissue remodeling. Abundant expression of MMPs leads to a number of tumorigenic processes including proliferation, angiogenesis, metastasis and invasion. Therefore, suppressing MMP expression is particularly important in cancer. Atorvastatin is a member of statin family, with cholesterol-lowering properties. Recently, it has emerged as a potential anticancer agent. Multiple researchers have reported promising results of atorvastatin use in cancer therapies. However, its effect on the expression of matrix metalloproteinases in breast cancer is unknown. In the present study, we have confirmed the apoptotic activity of atorvastatin on highly metastatic MDA-MB-231 triple negative breast cancer cells and investigated the gene expression of MMP-2/9. In this regard, MTT analysis was performed to evaluate cytotoxicity. Apoptotic activity was assessed by Annexin V binding and multicaspase assays. Western blot analysis was used to detect the apoptosis-related proteins. RT-PCR analysis was performed to evaluate the mRNA expression levels of MMP-2/9. Results indicated that atorvastatin reduces cell viability significantly at 5 µM after 48 h of treatment (p < 0.0001). It also induces caspase-dependent apoptosis, alters the expression of Bax and Bcl-2 in favour of apoptosis and stimulates cell cycle arrest at S phase (p < 0.05). Moreover, atorvastatin downregulates the mRNA expression of MMP-2 and MMP-9 significantly (p < 0.05). In conclusion, these results demonstrate for the first time that atorvastatin inhibits MMP-2 and MMP-9 gene expression in MDA-MB-231 cells, in addition to inducing caspase-dependent apoptosis.

Box-Behnken design optimization and in vitro cell based evaluation of piroxicam loaded core-shell type hybrid nanocarriers for prostate cancer.

In the present research, piroxicam entrapped core-shell lipid-polymer hybrid nanocarriers were developed and also evaluated in terms of nanoparticle features and cell-based in vitro efficacy on prostate cancer cells. Box-Behnken optimization approach was implemented to evaluate the impact of the input variables, namely phospholipid/PLGA ratio, total lipids/lecithin molar ratio, and piroxicam concentration, on two output variables: particle size and entrapment efficiency. Surface charge, size distribution, morphological structure of particles, drug release profiles, presence of outer lipid shell, thermal profile and possible interactions and storage stability of core-shell nanocarriers of piroxicam were studied as particle features. Cell viability, apoptosis and cell cycle arrest studies were utilized for in vitro cell-based evaluation of the core-shell nanosystems. The hybrid nanocarrier formulation with a particle size of 119.2 nm and an entrapment efficiency of 91.7% at the center point of the design was selected as the optimized formulation according to the desired function (d) method applied within the scope of the Box-Behnken design approach and RSM strategy. The cell viability and apoptosis experiments were performed on the optimized nanocarrier. In conclusion, this study demonstrates that the optimized core-shell nanoformulation of piroxicam is a more promising strategy in the treatment of prostate cancer compared to the pure molecule.

Hit evaluation results in 5-benzyl-1,3,4-thiadiazole-2-carboxamide based SIRT2-selective inhibitor with improved affinity and selectivity.

Sirtuin 2 (SIRT2), member of sirtuin family, belongs to class III histone deacetylases (HDACs) and is majorly cytosolic with occasional nuclear translocation. The enzymatic activity of SIRT2 is dependent on nicotinamide adenine dinucleotide (NAD+) and SIRT2 regulates post-translational modifications that are responsible for deacetylation of lysine residues in histone and non-histone substrates. SIRT2, thus affects most likely multiple cellular processes, such as signaling, gene expression, aging, autophagy, and has been identified as potential drug target in relation to inflammation, neurodegenerative diseases and cancer. Therefore, probing potential selective inhibitors is essential for the accurate understanding of enzyme functions. Here, we report a series of heteroaryl-2-carboxamide hybrids bearing substituted benzyl or substituted phenoxy group at the 5-position of the central heterocyclic ring. The synthesized compounds were screened against SIRT1-3 and MCF-7 human breast cancer cell line to evaluate their biological activity. The best SIRT2 inhibition profiles were displayed by ST29 (SIRT2 IC50 = 38.69 µM) and ST30 (SIRT2 IC50 = 43.29 µM) with excellent selectivity against SIRT2 over SIRT1 and SIRT3. Molecular docking study of the synthesized compounds into SIRT2 active site was performed to rationalize the remarkable SIRT2 inhibitory activity. Furthermore, we performed all-atom, explicit-solvent molecular dynamics (MD) simulations and end-point binding free energy calculations using molecular mechanics/generalized Born surface area (MM/GBSA) method to evaluate whether this design strategy was successfully deployed. The results implied that the binding poses and ligand affinities were predicted without significant loss of accuracy. Conclusively, the developed chemotypes were advocated as promising leads for SIRT2 inhibition and required further investigation for SIRT2-targeted drug discovery and development.

Ferroptosis: A Trusted Ally in Combating Drug Resistance in Cancer.

Ferroptosis, which is an iron-dependent, non-apoptotic cell death mechanism, has recently been proposed as a novel approach in cancer treatment. Bearing distinctive features and its exclusive mechanism have put forward the potential therapeutic benefit of triggering this newly discovered form of cell death. Numerous studies have indicated that apoptotic pathways are often deactivated in resistant cells, leading to a failure in therapy. Hence, alternative strategies to promote cell death are required. Mounting evidence suggests that drug-resistant cancer cells are particularly sensitive to ferroptosis. Given that cancer cells consume a higher amount of iron than healthy ones, ferroptosis not only stands as an excellent alternative to trigger cell death and reverse drug-resistance, but also provides selectivity in therapy. This review focuses specifically on overcoming drugresistance in cancer through activating ferroptotic pathways and brings together the relevant chemotherapeutics-based and nanotherapeutics-based studies to offer a perspective for researchers regarding the potential use of this mechanism in developing novel therapeutic strategies.

Increased endoglin levels correlated with angiogenesis-associated angiopoietin-2 in haemophilia patients.

INTRODUCTION: Haemophilia is a bleeding disorder that occurs due to the deficiency of coagulation factors, and the angiogenesis process is an important process underlying the pathophysiology of haemophilic arthropathy. The role of the new adipocytokine endoglin (ENG) in patients with haemophilia is not yet known. AIM: The aim of this study is to evaluate the association between ENG protein and angiogenesis-related cytokines in patients with haemophilia for the first time. METHODS: Plasma protein levels and mRNA expressions of ENG and various angiogenesis-associated cytokines were compared in blood samples collected from 28 patients with haemophilia A or B and 29 healthy volunteers. The relationship between the cytokines and ENG were determined by correlation analysis. RESULTS: Plasma ENG levels and angiogenic markers were found to be significantly higher in patients with haemophilia compared to controls. Real-time PCR studies showed that mRNA expressions of ENG, vascular endothelial growth factor A, hypoxia-inducible factor A, and prostaglandin E2 increased in patients with haemophilia. Correlation analysis showed a significant positive correlation between ENG and angiopoietin-2 levels in the haemophilia group. Besides, a significant decrease in annexin-V binding to platelets in haemophilia patients compared to control was found to be related to the bleeding profiles in the patients. CONCLUSIONS: This study determined that ENG protein may be involved in the formation of angiogenesis in haemophilia patients and its effects may be related to angiogenetic marker angiopoietin-2 in this process. Our findings contribute to the literature during the determination of target proteins in haemophilia treatment.

Investigation of molecular mechanisms underlying the antiproliferative effects of colchicine against PC3 prostate cancer cells.

This work examined the cytotoxic effects of colchicine on PC3 cells and elucidated the possible underlying mechanisms of its cytotoxicity. The cells were exposed to colchicine at different concentrations ranging from 1 to 100 ng/mL for 24 h, and it showed considerable cytotoxicity with an IC50 value of 22.99 ng/mL. Mechanistic studies also exhibited that colchicine treatment results in cell cycle arrest at the G2/M phase as well as decreased mitochondrial membrane potential and increased early and late apoptotic cells. The apoptotic and DNA-damaging effects of colchicine have also been verified by fluorescence imaging and ELISA experiments, and they revealed that while colchicine treatment significantly modulated expression as increases in Bax, cleaved caspase 3, cleaved PARP, and 8-hydroxy-desoxyguanosine levels and as a decrease of BCL-2 protein expression. Besides, colchicine treatment significantly increased the total oxidant (TOS) level, which is a signal of oxidative stress and potential cause of DNA damage. Finally, the results of quantitative real-time PCR experiments demonstrated that colchicine treatment concentration-dependently suppressed MMP-9 mRNA expression. Overall, colchicine provides meaningful cytotoxicity on PC3 cells due to induced oxidative stress, reduced mitochondrial membrane potential, increased DNA damage, and finally increased apoptosis in PC3 cells. Nevertheless, further research needs to be conducted to assess the potential of colchicine as an anticancer drug for the treatment of prostate cancer.

Hit-to-lead optimization on aryloxybenzamide derivative virtual screening hit against SIRT.

Sirtuins (SIRTs) are a class of nicotinamide adenine dinucleotide (NAD+)-dependent protein histone deacetylases (HDACs) that are evolutionarily conserved from bacteria to mammals. This group of enzymes catalyses the reversible deacetylation of lysine residues in the histones or non-histone substrates using NAD+ as a cosubstrate. Numerous studies have demonstrated that the aberrant enzymatic activity of SIRTs has been linked to various diseases like diabetes, cancer, and neurodegenerative disorders. Previously, we performed a pharmacophore-based virtual screening campaign and an aryloxybenzamide derivative (1) displaying SIRT1/2 inhibitory effect was identified as a hit compound. In the current study, the hit-to-lead optimization on the hit compound was explored in order to improve the SIRT binding and inhibition. Fourteen compounds, ten of which were new, have been synthesized and subjected to in vitro biological evaluation for their inhibitory activity against SIRT1-3. By the structural modifications performed, a significant improvement was observed in selective SIRT1 inhibition for ST01, ST02, and ST11 compared to that of the hit compound. The highest SIRT2 inhibitory activity was observed for ST14, which was designed according to compatibility with pharmacophore model developed for SIRT2 inhibitors and thus, providing the interactions required with key residues in SIRT2 active site. Furthermore, ST01, ST02, ST11, and ST14 were subjected to in vitro cytotoxicity assay against MCF-7 human breast cancer cell line to determine the influence of the improvement in SIRT1/2 inhibition along with the structural modifications on the cytotoxic properties of the compounds. The cytotoxicity of the compounds was found to be correlated with their SIRT inhibitory profiles indicating the effects of SIRT1/2 inhibition on cancer cell viability. Overall, this study provides structural insights for further inhibitor improvement.

Layer by layer assembly of core-corona structured solid lipid nanoparticles with ß-cyclodextrin polymers.

This study aims to design and characterize the layer-by-layer assembly of core-corona nanoarchitecture for novel surface-modified solid lipid nanoparticles. Oppositely charged ß-cyclodextrin polymers were used to build corona structure onto lipid core, and the particle size, polydispersity index, and zeta potential of SLN with polymer layers were evaluated. Morphology of surface-modified SLN was identified using TEM. The effect of polymer coating on drug release pattern was investigated by in-vitro release studies. The biocompatibility of the novel SLN systems was assessed on various healty cell lines using in vitro cytotoxicity assay. The presence of the oppositely charged polymer layers was found to be effective on alteration of zeta potential from negative to positive values and an increased surface charge density was achieved in comparison to core SLN. The results also revealed that the drug release is mainly controlled by diffusion and ß-cyclodextrin polymers could enhance the slow/controlled release of drug. Cytotoxicity assay results suggested that the novel, hierarchical core-corona structured SLNs don't have cytotoxic effects on healthy cells and can be safely used as drug carriers. Overall, the layer-by-layer assembly of ß-cyclodextrin polymers is promising for designing surface-modified nanoarchitectures of lipid nanoparticles that may be applied via many administration routes.

Seseli petraeum M. Bieb. (Apiaceae) Significantly Inhibited Cellular Growth of A549 Lung Cancer Cells through G0/G1 Cell Cycle Arrest.

Seseli L. is an important genus of the Apiaceae family, with a large number of aromatic species. It is used in traditional medicine extensively, but there is quite limited information on their phytochemicals and biological activities. Seseli petraeum M. Bieb. grows in Northern Anatolia, and there are no phytochemical studies on this species. In the present study, we aimed to investigate the effect of the extracts of S. petraeum on A549 lung cancer cell proliferation. For this purpose, the antiproliferative effect was determined via MTT assay, and the extracts obtained from the root of S. petraeum showed a significant inhibitory effect on cell proliferation. The hexane extract of the root exhibited potent inhibition on A549 cancer cell growth at the 24th hour with 3.432 mg/mL IC50 value. The results also showed that the hexane extract had displayed cytotoxic effect through an arrest at the G0/G1 phase of the cell cycle and induced apoptosis as well as DNA damage of A549 cells. Consequently, this study demonstrated the antiproliferative potential of the extracts from S. petraeum, especially hexane extract from the roots. Further studies are required to identify the mechanisms underlying these effects.

Potentiation of the Effect of Lonidamine by Quercetin in MCF-7 human breast cancer cells through downregulation of MMP-2/9 mRNA Expression.

Combination therapies are becoming increasingly important to develop an effective treatment in cancer. Lonidamine is frequently used in cancer treatment, but it's often preferred to be used in combination with other drugs because of its side effects. In the present study, the efficacy of the combination of lonidamine with quercetin, a flavonoid of natural origin, on human MCF-7 breast cancer cells was evaluated. The results showed that the combined use of the compounds significantly increased cytotoxicity compared to administration alone (p<0.0001). In addition, while lonidamine induced a cell cycle arrest in the G2/M phase, administration of quercetin and its combination with lonidamine arrested the cell division at S point, indicating the synergistic strength of quercetin on cytotoxicity. The combination of quercetin and lonidamine significantly induced apoptosis of MCF-7 cells (p<0.0001) and increased caspase levels (p<0.0001). In this study, the combination of quercetin and lonidamine has been evaluated for the first time and the combination treatment decreased MMP-2/-9 mRNA expression more potently than the effects of the compounds alone. The results showed that lonidamine was more effective when combined with quercetin, and their combination may be a candidate for a novel strategy of treatment for breast cancer.