Antiproliferative and Pro-Apoptotic Activity and Tubulin Dynamics Modulation of 1H-Benzimidazol-2-yl Hydrazones in Human Breast Cancer Cell Line MDA-MB-231.

(1) Background: The aim of the work is the evaluation of in vitro antiproliferative and pro-apoptotic activity of four benzimidazole derivatives containing colchicine-like and catechol-like moieties with methyl group substitution in the benzimidazole ring against highly invasive breast cancer cell line MDA-MB-231 and their related impairment of tubulin dynamics. (2) Methods: The antiproliferative activity was assessed with the MTT assay. Alterations in tubulin polymerization were evaluated with an in vitro tubulin polymerization assay and a docking analysis. (3) Results: All derivatives showed time-dependent cytotoxicity with IC50 varying from 40 to 60 µM after 48 h and between 13 and 20 µM after 72 h. Immunofluorescent and DAPI staining revealed the pro-apoptotic potential of benzimidazole derivatives and their effect on tubulin dynamics in living cells. Compound 5d prevented tubulin aggregation and blocked mitosis, highlighting the importance of the methyl group and the colchicine-like fragment. (4) Conclusions: The benzimidazole derivatives demonstrated moderate cytotoxicity towards MDA-MB-231 by retarding the initial phase of tubulin polymerization. The derivative 5d containing a colchicine-like moiety and methyl group substitution in the benzimidazole ring showed potential as an antiproliferative agent and microtubule destabilizer by facilitating faster microtubule aggregation and disrupting cellular and nuclear integrity.

Tuning of the Anti-Breast Cancer Activity of Betulinic Acid via Its Conversion to Ionic Liquids.

Betulinic acid (BA) is a natural pentacyclic triterpene with diverse biological activities. However, its low water solubility limits its pharmaceutical application. The conversion of pharmaceutically active molecules into ionic liquids (ILs) is a promising strategy to improve their physicochemical properties, stability, and/or potency. Here, we report the synthesis and characterization of 15 novel ILs containing a cation ethyl ester of a polar, non-polar, or charged amino acid [AAOEt] and an anion BA. Except for [ValOEt][BA], we observed preserved or up to 2-fold enhanced cytotoxicity toward hormone-dependent breast cancer cells MCF-7. The estimated IC50 (72 h) values within the series varied between 4.8 and 25.7 µM. We found that the most cytotoxic IL, [LysOEt][BA]2, reduced clonogenic efficiency to 20% compared to that of BA. In addition, we evaluated the effect of a 72 h treatment with BA or [LysOEt][BA]2, the most cytotoxic compound, on the thermodynamic behavior of MCF-7 cells. Based on our data, we suggest that the charged amino acid lysine included in the novel ILs provokes cytotoxicity by a mechanism involving alteration in membrane lipid organization, which could be accompanied by modulation of the visco-elastic properties of the cytoplasm.

Special Issue "Role of Apoptosis and Cellular Senescence in Cancer and Aging".

The intention of this Special Issue is to elucidate the role of apoptosis and cellular senescence in different pathological processes, such as cancer and aging [...].

Endothelial Senescence and Its Impact on Angiogenesis in Alzheimer's Disease.

Endothelial cells are constantly exposed to environmental stress factors that, above a certain threshold, trigger cellular senescence and apoptosis. The altered vascular function affects new vessel formation and endothelial fitness, contributing to the progression of age-related diseases. This narrative review highlights the complex interplay between senescence, oxidative stress, extracellular vesicles, and the extracellular matrix and emphasizes the crucial role of angiogenesis in aging and Alzheimer's disease. The interaction between the vascular and nervous systems is essential for the development of a healthy brain, especially since neurons are exceptionally dependent on nutrients carried by the blood. Therefore, anomalies in the delicate balance between pro- and antiangiogenic factors and the consequences of disrupted angiogenesis, such as misalignment, vascular leakage and disturbed blood flow, are responsible for neurodegeneration. The implications of altered non-productive angiogenesis in Alzheimer's disease due to dysregulated Delta-Notch and VEGF signaling are further explored. Additionally, potential therapeutic strategies such as exercise and caloric restriction to modulate angiogenesis and vascular aging and to mitigate the associated debilitating symptoms are discussed. Moreover, both the roles of extracellular vesicles in stress-induced senescence and as an early detection marker for Alzheimer's disease are considered. The intricate relationship between endothelial senescence and angiogenesis provides valuable insights into the mechanisms underlying angiogenesis-related disorders and opens avenues for future research and therapeutic interventions.

A Standardized Extract of Petasites hybridus L., Containing the Active Ingredients Petasins, Acts as a Pro-Oxidant and Triggers Apoptosis through Elevating of NF-κB in a Highly Invasive Human Breast Cancer Cell Line.

BACKGROUND: Common butterbur (Petasites hybridus L.) is a traditional medicinal plant with numerous therapeutic properties among which is its recently uncovered anti-tumor activity. The present study aims to examine the activity of a standardized Bulgarian Petasites hybridus L. root extract, containing the active ingredients petasins, on the human breast cancer cell line MDA-MB-231 and non-cancerous MCF-10A cells. Specifically, we examined cell death, oxidative stress, and nuclear factor kappa-B (NF-κB) signaling. METHODS: A standardized butterbur powdered extract containing a minimum of 15% petasins was used. A lipophilic extract was obtained from subterranean portion of the plant of Bulgarian populations of Petasites hybridus using liquid-liquid extraction after completely removing pyrrolizidine alkaloids. The induction of apoptosis and necrosis was analyzed by flow cytometry, and oxidative stress biomarkers and NF-κB were measured using enzyme-linked immunosorbent assay (ELISA). RESULTS: Petasites hybridus L. root extract triggered apoptosis in a cancer-specific fashion and induced a moderate oxidative stress characterized by diminished glutathione (GSH) levels and elevated malondialdehyde (MDA) levels in MDA-MB-231 72 h after treatment. NF-κB levels were higher in cancer cells after treatment with IC50 and IC75 doses, this suggested that the NF-κB pathway was activated in response to oxidative stress leading to the induction of apoptosis. MCF-10A cells were affected to a lesser extent by the Petasites hybridus extract, and the adaptive response of their antioxidant defense system halted oxidative stress. CONCLUSIONS: Overall, these results indicate that Petasites hybridus L. root extract selectively acts as a pro-oxidant in breast cancer cells and thus represents a potential therapeutic option for cancer treatment with fewer side effects.

Novel Fluorescent Benzimidazole-Hydrazone-Loaded Micellar Carriers for Controlled Release: Impact on Cell Toxicity, Nuclear and Microtubule Alterations in Breast Cancer Cells.

Fluorescent micellar carriers with controlled release of a novel anticancer drug were developed to enable intracellular imaging and cancer treatment simultaneously. The nanosized fluorescent micellar systems were embedded with a novel anticancer drug via the self-assembling behavior of well-defined block copolymers based on amphiphilic poly(acrylic acid)-block-poly(n-butyl acrylate) (PAA-b-PnBA) copolymer obtained by Atom Transfer Radical Polymerization (ATRP) and hydrophobic anticancer benzimidazole-hydrazone drug (BzH). Through this method, well-defined nanosized fluorescent micelles were obtained consisting of a hydrophilic PAA shell and a hydrophobic PnBA core embedded with the BzH drug due to the hydrophobic interactions, thus reaching very high encapsulation efficiency. The size, morphology, and fluorescent properties of blank and drug-loaded micelles were investigated using dynamic light scattering (DLS), transmission electron microscopy (TEM), and fluorescent spectroscopy, respectively. Additionally, after 72 h of incubation, drug-loaded micelles released 3.25 µM of BzH, which was spectrophotometrically determined. The BzH drug-loaded micelles were found to exhibit enhanced antiproliferative and cytotoxic effects on MDA-MB-231 cells, with long-lasting effects on microtubule organization, with apoptotic alterations and preferential localization in the perinuclear space of cancer cells. In contrast, the antitumor effect of BzH alone or incorporated in micelles on non-cancerous cells MCF-10A was relatively weak.

New Indole-3-Propionic Acid and 5-Methoxy-Indole Carboxylic Acid Derived Hydrazone Hybrids as Multifunctional Neuroprotectors.

In light of the known neuroprotective properties of indole compounds and the promising potential of hydrazone derivatives, two series of aldehyde-heterocyclic hybrids combining those pharmacophores were synthesized as new multifunctional neuroprotectors. The obtained derivatives of indole-3-propionic acid (IPA) and 5-methoxy-indole carboxylic acid (5MICA) had good safety profiles: Hemolytic effects < 5% (200 µM) and IC50 > 150 µM were found in the majority of the SH-SY5Y and bEnd3 cell lines. The 2,3-dihydroxy, 2-hydroxy-4-methoxy, and syringaldehyde derivatives of 5MICA exhibited the strongest neuroprotection against H2O2-induced oxidative stress in SH-SY5Y cells and 6-OHDA-induced neurotoxicity in rat-brain synaptosomes. All the compounds suppressed the iron-induced lipid peroxidation. The hydroxyl derivatives were also the most active in terms of deoxyribose-degradation inhibition, whereas the 3,4-dihydroxy derivatives were able to decrease the superoxide-anion generation. Both series of compounds showed an increased inhibition of hMAO-B, with greater expression detected in the 5MICA hybrids. The in vitro BBB model with the bEnd3 cell line showed that some compounds increased the permeability of the endothelial monolayer while maintaining the tight junctions. The combined results demonstrated that the derivatives of IPA and 5MICA showed strong neuroprotective, antioxidant, MAO-B inhibitory activity and could be considered as prospective multifunctional compounds for the treatment of neurodegenerative disorders.

Oxidative Stress and Aging as Risk Factors for Alzheimer's Disease and Parkinson's Disease: The Role of the Antioxidant Melatonin.

Aging and neurodegenerative diseases share common hallmarks, including mitochondrial dysfunction and protein aggregation. Moreover, one of the major issues of the demographic crisis today is related to the progressive rise in costs for care and maintenance of the standard living condition of aged patients with neurodegenerative diseases. There is a divergence in the etiology of neurodegenerative diseases. Still, a disturbed endogenous pro-oxidants/antioxidants balance is considered the crucial detrimental factor that makes the brain vulnerable to aging and progressive neurodegeneration. The present review focuses on the complex relationships between oxidative stress, autophagy, and the two of the most frequent neurodegenerative diseases associated with aging, Alzheimer's disease (AD) and Parkinson's disease (PD). Most of the available data support the hypothesis that a disturbed antioxidant defense system is a prerequisite for developing pathogenesis and clinical symptoms of ADs and PD. Furthermore, the release of the endogenous hormone melatonin from the pineal gland progressively diminishes with aging, and people's susceptibility to these diseases increases with age. Elucidation of the underlying mechanisms involved in deleterious conditions predisposing to neurodegeneration in aging, including the diminished role of melatonin, is important for elaborating precise treatment strategies for the pathogenesis of AD and PD.

Significance of Antioxidants on Aging and Neurodegeneration.

The hallmark of aging is an organism's difficulty to maintain proper homeostasis, leading to a disrupted balance between the endogenous antioxidant system and the production of free radicals, a progressive inflammatory process, and increased susceptibility to (neurodegenerative diseases [...].

Impact of Melatonin Deficit on Emotional Status and Oxidative Stress-Induced Changes in Sphingomyelin and Cholesterol Level in Young Adult, Mature, and Aged Rats.

The pineal gland regulates the aging process via the hormone melatonin. The present report aims to evaluate the effect of pinealectomy (pin) on behavioral and oxidative stress-induced alterations in cholesterol and sphingomyelin (SM) levels in young adult, mature and aging rats. Sham and pin rats aged 3, 14 and 18 months were tested in behavioral tests for motor activity, anxiety, and depression. The ELISA test explored oxidative stress parameters and SM in the hippocampus, while total cholesterol was measured in serum via a commercial autoanalyzer. Mature and aged sham rats showed low motor activity and increased anxiety compared to the youngest rats. Pinealectomy affected emotional responses, induced depressive-like behavior, and elevated cholesterol levels in the youngest rats. However, removal of the pineal gland enhanced oxidative stress by diminishing antioxidant capacity and increasing the MDA level, and decreased SM level in the hippocampus of 14-month-old rats. Our findings suggest that young adult rats are vulnerable to emotional disturbance and changes in cholesterol levels resulting from melatonin deficiency. In contrast, mature rats with pinealectomy are exposed to an oxidative stress-induced decrease in SM levels in the hippocampus.

The Anticonvulsant Effect of a Novel Indole-Related Compound in the Kainate-Induced Status Epilepticus in Mice: The Role of the Antioxidant and Anti-inflammatory Mechanism.

We synthesized a series of novel indole compounds containing aroylhydrazone moieties and evaluated them in mice to check their anticonvulsant activity. In the present study the most potent C3-modified derivative 3e, containing 2-furyl fragment was evaluated in kainate (KA)-induced status epilepticus (SE) and the consequences on oxidative stress and inflammation in the hippocampus in mice were explored. Melatonin was used as positive control while the melatonin receptor antagonist Luzindol was studied alone or in combination with melatonin or 3e, respectively. After intraperitoneal (i.p.) pre-treatment with melatonin 3e, Luzindol + melatonin and Luzindol + 3e for 7 days (melatonin and 3e-30 mg kg-1 or 60 mg kg-1, Luzindol 10 mg kg-1) the animals were i.p. injected with KA (30 mg kg-1, i.p.). The 3e decreased the SE-induced seizure intensity while melatonin suppressed seizures at the higher dose of 60 mg kg-1. Luzindol blocked the anticonvulsant effect of both Mel and 3e. The dose-dependent antioxidant effect of 3e measured by reduced glutathione (GSH) and total GSH in the hippocampus, was comparable to the effect of melatonin. Luzindol fully blocked the effect of melatonin but affected partially the antioxidant activity of 3e. The KA-induced increased amplifier of neuroinflammation high-mobility group box protein 1 (HMGB1) was neither alleviated by melatonin, nor by 3e. The activation by this DNA-binding protein receptor for advanced glycation end products (RAGE) was not affected by SE, melatonin and 3e pre-treatment. Our results suggest that the novel indole derivate 3e, containing 2-furyl fragment, might be clinically useful as an adjunct therapy against SE and concomitant oxidative stress.

The Role of Melatonin on Behavioral Changes and Concomitant Oxidative Stress in icvAß1-42 Rat Model with Pinealectomy.

One of the pathological hallmarks of Alzheimer's disease (AD) associated with its progression that contributes to ß-amyloid (Aß) generation is oxidative stress (OS). Clinical data suggest that melatonin is a potent antioxidant that might be effective in the adjunctive therapy of this neurodegenerative disease. The present study aimed to explore the role of melatonin on behavioral changes and markers of OS in three rat models, namely, pinealectomy (pin) model of melatonin deficit, intracerebroventricular (icv)Aß1-42 model of AD, and combination of both pin and Aß1-42 model (pin+icvAß1-42). The chronic injection with vehicle/melatonin (50 mg/kg, i.p. for 40 days) started on the same day of sham/pin and icv vehicle/Aß1-42 infusion procedures. Anxiety in the open field and the elevated plus-maze test and cognitive responses in the object recognition test were tested between the 30th-35th day after the surgical procedures. Markers of OS in the frontal cortex (FC) and hippocampus were detected by the ELISA method. Melatonin treatment corrected the exacerbated anxiety response only in the pin+icvAß1-42 model while it alleviated the cognitive impairment in the three models. Pinealectomy disturbed the antioxidant system via enhanced SOD activity and decreased GSH levels both in the FC and hippocampus. The Aß1-42 model decreased the SOD activity in the FC and elevated the MDA level in the two brain structures. The pin+icvAß1-42 model impaired the antioxidant system and elevated lipid peroxidation. Melatonin supplementation restored only the elevated MDA level of icvAß1-42 and pin+icvAß1-42 model in the hippocampus. In conclusion, our study reveals that the pin+icvAß1-42 rat model triggers more pronounced anxiety and alterations in markers of OS that may be associated with melatonin deficit concomitant to icvAß1-42-induced AD pathology.

Effect of Erufosine on Membrane Lipid Order in Breast Cancer Cell Models.

Alkylphospholipids are a novel class of antineoplastic drugs showing remarkable therapeutic potential. Among them, erufosine (EPC3) is a promising drug for the treatment of several types of tumors. While EPC3 is supposed to exert its function by interacting with lipid membranes, the exact molecular mechanisms involved are not known yet. In this work, we applied a combination of several fluorescence microscopy and analytical chemistry approaches (i.e., scanning fluorescence correlation spectroscopy, line-scan fluorescence correlation spectroscopy, generalized polarization imaging, as well as thin layer and gas chromatography) to quantify the effect of EPC3 in biophysical models of the plasma membrane, as well as in cancer cell lines. Our results indicate that EPC3 affects lipid-lipid interactions in cellular membranes by decreasing lipid packing and increasing membrane disorder and fluidity. As a consequence of these alterations in the lateral organization of lipid bilayers, the diffusive dynamics of membrane proteins are also significantly increased. Taken together, these findings suggest that the mechanism of action of EPC3 could be linked to its effects on fundamental biophysical properties of lipid membranes, as well as on lipid metabolism in cancer cells.

Evaluation of neurobiological and antioxidant effects of novel melatonin analogs in mice.

Based on the pharmacophore model of melatonin (MT1) receptor, we recently synthesized a series of indole derivatives that showed anticonvulsant activity with low neurotoxicity and hepatotoxicity in rodents. In the present study, the three most potent C3-modified derivatives with hydrazine structure 3c, 3e, and 3f, with 2-chlorophenyl, 2-furyl, and 2-thienyl fragments, respectively, were selected, and their neurobiological activity was explored in mice. In Experiment #1, the dose-dependent anxiolytic effect of a single i.p. administration of the novel compounds at doses of 10, 30, and 60 mg/kg were studied in the open field (OF) test. In Experiment#2, the analgesic effect of 3c, 3e, and 3f (30-100 mg/kg) was tested in the hot plate test and formalin test. Experiment#3 was designed to assess the antidepressant-like activity of 3c, 3e, and 3f (10-60 mg/kg). The forced swimming test (FST) and tail suspension test (TST)-induced effect on markers of oxidative stress in the frontal cortex (FC), and the hippocampus was evaluated. Melatonin was used in the same doses as melatonin analogs in all three experiments as a positive control. Desipramine (10 mg/kg) was also applied as a control in the FST. The three melatonin analogs bearing hydrazide/hydrazone substitution at 3C of the indol scaffold demonstrated improved antidepressant-like activity compared to the melatonin. The tested substances are devoided of anxiolytic effects. The antioxidant activity of the melatonin analogs and analgesic potential is comparable to that of melatonin. The 3C substitution with hydrazide/hydrazone moiety substantially contributes to the antidepressant and antioxidant activity of the melatonin analogs.

Dimethylsphingosine and miltefosine induce apoptosis in lung adenocarcinoma A549 cells in a synergistic manner.

Lung cancer is one of the most common and lethal types of oncological diseases. Despite the advanced therapeutic approaches, the prognosis for lung cancer still remains poor. Apparently, there is an imperative need for more efficient therapeutic strategies. In this work we report that concurrent treatment of human adenocarcinoma A549 cells with specific concentrations of two antitumor agents, the sphingosine kinase 1 inhibitor N, N dimethylsphingosine (DMS) and the alkylphosphocholine miltefosine, induced synergistic cytotoxic effect, which was confirmed by calculation of the combination index. The simultaneous action of these agents, induced significant decrease of A549 cell number, as well as pronounced morphological alterations. Combined drugs caused substantial apoptotic events, and significant reduction of the pro-survival marker sphingosine- 1-phosphate (S1P), when compared to the individual treatments with each of the anticancer drugs alone. Miltefosine is known to affect the synthesis of choline-containing phospholipids, including sphingomyelin, but we report for the first time that it also reduces S1P. Here we suggest a putative mechanism underlying the effect of miltefosine on sphingosine kinase 1, involving miltefosine-induced inhibition of protein kinase C. In conclusion, our findings provide a possibility for treatment of lung cancer cells with lower concentrations of the two antitumor drugs, DMS and miltefosine, which is favorable, regarding their potential cytotoxicity to normal cells.

Study of potential biomedical application of sol-gel derived Zn-doped SiO2-hydroxypropyl cellulose nanohybrids.

A series of Zn-doped hybrid materials based on silica from tetraethoxysilane (TEOS) and hydroxypropyl cellulose (HPC) were prepared by a sol-gel route. The structure, morphology and thermal behavior of synthesized hybrids were characterized by infrared (IR) spectroscopy, ultraviolet-visible spectroscopy (UV-Vis), transmission electron microscopy (TEM) and differential thermal analysis with thermogravimetric analysis (DTA/TG). The obtained materials were investigated for a potential biomedical application. The antibacterial properties of hybrids were investigated by measuring the inhibition zones formed around the materials containing different zinc content in presence of reference strains of Gram-positive and Gram-negative bacteria. The biocompatibility tests showed no cytotoxicity and genotoxicity, as well as no changes in actin cytoskeleton organization for hybrids with Zn content below 5 wt%.

New cycloartane triterpenes from bioactive extract of propolis from Pitcairn Island.

Dichloromethane extract of propolis (DCME) originating from Pitcairn Island demonstrated potent cytotoxicity against triple-negative MDA-MB-231 human breast carcinoma cells. The results from MTT assay showed that DCME inhibits the growth of the cancer cells in a dose- and time-dependent manner and upon the cell growth inhibition propolis extract provoked apoptotic changes in the cell nuclei. A detailed chemical investigation of DCME led to the isolation of four new cycloartane triterpenes (1-4), along with 17 known compounds (5-21). The structures of the new compounds were elucidated by means of extensive analysis of their spectroscopic data and comparison with those reported for their analogues. In vitro antimicrobial activity of new compounds (1-4) along with the DCME against four human pathogens was evaluated. All tested constituents except compound 2 were highly active against Escherichia coli with MIC 64 µg/ml. Compound 1 exhibited high antifungal activity against Candida albicans with potency close to that of the positive control (amphotericin B). The DCME showed very good antimicrobial activity against Staphylococcus aureus, Escherichia coli and Candida albicans. This is the first study on propolis from Pitcairn Island.

Angiogenic potential of endothelial and tumor cells seeded on gelatin-based hydrogels in response to electrical stimulations.

Angiogenesis is one of the key processes during development, wound healing and tumor formation. Prerequisite for its existence is the presence of endogenous electrical fields (EFs) generated by active ion transport across polarized epithelia and endothelia, and appearance of the transcellular potentials. During angiogenesis cellular factor as endothelial growth factor (VEGF), synthesis of adhesive proteins and membrane metalloproteinases (MMPs) govern the angiogenic response to different external stimuli as biomaterials interactions and/or exogenous EF. Gelatin-based hydrogels with elasticities comparable to human tissues have shown to influence cell behavior as well as cell attachment, protein synthesis, VEGF and MMP's production after the application of EF. Gelatin-based matrices with 3 (G10_LNCO3), 5 (G10_LNCO5), and 8 (G10_LNCO8) fold excess of isocyanate groups per mol of amine groups present in gelatin were used. Human umbilical endothelial cells (HUVEC) (Lonza Basel, Switzerland) and highly invasive breast cancer MDA-MB-231 cells (ATCC®HTB-26TM) were used. For an estimation of the amount of VEGF released from cells a commercially available VEGF ELISA (Thermo Fisher Scientific, Germany) kit was used. Fibronectin (FN) enzyme immunoassay (EIA) was used to analyze the secreted amount of FN by cells seeded on the materials. Secreted MMPs were analyzed by zymography. Gelatin-based hydrogels attracted HUVEC adhesion and diminished the adhesion of MDA-MB-231 cells. The applied direct current (DC) EF induced an almost 5-fold increase in VEGF production by HUVEC seeded on gelatin-based hydrogels, while in contrast, the applied EF decreased the production of VEGF by cancer cells. FN synthesis was elevated in HUVEC cells seeded on gelatin-based materials in comparison to FN synthesis by cancer cells. HUVEC seeded on gelatin hydrogels showed an expression mainly of MMP-2. The application of EF increased the production of MMP-2 in HUVEC seeded on gelatin materials. In contrast, for MDA-MB-231 the production of MMPs on gelatin materials was lower compared to control materials. With the application of EF the levels of MMP-9 decreased but MMP-2 expression raised significantly for gelatin materials. Overall, the results showed that studied gelatin materials suppressed attachment of cancerous cells, as well as suppressed their angiogenic potential revealed by decreased VEGF and MMP production. Thus, this study approved gelatin-based hydrogels with proper elasticity characteristics and different degradation behavior as useful matrices for use in vascular tissue regeneration or in restriction of tumor growth after tumor resection.

Statins and Alkylphospholipids as New Anticancer Agents Targeting Lipid Metabolism.

The partial efficacy and high toxicity of the current anticancer chemotherapeutics as well as the development of multiple drug resistance are the major problems in cancer therapy. Therefore, there is an emergency need for the development of novel well-tolerated anticancer agents with different mode of action that could be successfully used in combination with other drugs as an adjuvant therapy. The inhibition of intracellular signaling pathways associated with cancer growth and invasiveness is a main therapeutic approach in cancer treatment. It is well known that lipid metabolism is involved in the regulation of key cellular processes such as proliferation, differentiation and apoptosis. Statins and alkylphospholipids are both relatively new synthetic agents with considerable anticancer properties that disturb lipid metabolism and subsequently modulate proliferation and cell survival signaling pathways, leading to apoptosis. Numerous in vitro and in vivo studies have shown promising results for the use of statins and alkylphospholipids as potential therapeutic agents in the treatment of various human malignancies. However, more investigations and clinical trials are needed to assess their optimal safe dose and maximal efficacy and better understand the molecular mechanisms underlying the antitumor effects of these drugs.

Novel electrically conducting 2-hydroxyethylcellulose/polyaniline nanocomposite cryogels: Synthesis and application in tissue engineering.

Novel electrically conducting 2-hydroxyethylcellulose/polyaniline (HEC/PANI) nanocomposite cryogels were fabricated via the combination of cryogenic treatment and photochemical crosslinking. PANI nanofillers (one-dimentional tubes and three-dimentional particles) were synthesized via oxidative polymerization of aniline in aqueous media and, then, embedded in the HEC matrix. The effect of PANI content and morphology on the gel fraction yield and electrical conductivity of material was studied. Nanocomposite cryogels of high gel fraction yield (65-95%) and rather high electrical conductivity (0.02-0.1S/m) were obtained by using a relatively small amount (0.5-3wt.% to HEC) of pre-formed PANI nanofillers. The behavior of L929 cells adhered on HEC/PANI cryogels in the presence of electric field were also investigated. Cytotoxicity test showed very good survival and proliferation of cells on cryogels, while the electrical stimulation triggered changes in cell morphology as well as a specific alignment of cells in parallel to the electrical field.