Cytotoxicity and induction of apoptosis of human breast cancer cells by novel platinum(II) complexes

The current work investigates the influence of novel dinuclear platinum(II) compounds of structure: Pt₂(3-ethylpyridine)₄(berenil)₂ (Pt10) and Pt₂(3-butylpyridine)₄(berenil)₂ (Pt11) on growth and viability of MDA-MB-231 and MCF-7 breast cancer cells as well as their putative mechanism of cytotoxicity. Evaluation of the cytotoxicity of Pt10 and Pt11 employing a MTT assay and inhibition of [³H]thymidine incorporation into DNA in both MDA-MB-231 and MCF-7 breast cancer cells demonstrated that these compounds were more potent antiproliferative agents than cisplatin. In our study the induction of apoptosis by Pt10 and Pt11 in human breast cancer cells was confirmed by several biochemical markers, such as: phosphatidylserine externalization, loss of mitochondrial membrane potential ΔΨ_m, caspase-3, -8, -9 activity, and DNA degradation. Pt10 and Pt11 induce apoptosis of breast cancer cells via mechanisms dependent on caspases activation and associated with mitochondrial membrane potential disruption.     

Platinum complexes with 5-methyl-5(4-pyridyl)hydantoin and its 3-methyl derivatives: synthesis and cytotoxic activity - quantitative structure-activity relationships

3,5‐Dimethyl‐5‐(4‐pyridyl)hydantoin (L) and its platinum(II) and platinum(IV) complexes with the general formula cis‐[PtL₂X₂] · n H₂O and [PtL₂Cl₄], where X?Cl, I and n = 2‐4 were synthesized. A new Pt(IV) complex with 5‐methyl‐5‐(4‐pyridyl)hydantoin (L′) with the formula cis‐[Pt(L′)₂Cl₂(OH)₂] · 5 H₂O was also synthesized. The novel compounds were characterized by elemental analysis, IR, ¹H‐, ¹³C‐, ¹⁹⁵Pt‐NMR spectra and molar conductivity. The cytotoxic effects of these complexes were examined on three human tumor cell lines by MTT‐dye reduction assay. These four new Pt(II) and Pt(IV) complexes and a set of another twelve Pt(II), Pt(IV), and Pd(II) complexes previously synthesized and tested were compiled and a QSAR model was derived in order to direct the further rational synthesis.     

Ouabain induces apoptotic cell death in human prostate DU 145 cancer cells through DNA damage and TRAIL pathways

Ouabain, a cardiotonic steroid and specific Na⁺/K⁺‐ATPase inhibitor, has a potential to induce cancer cell apoptosis but the mechanisms of apoptosis induced by ouabain are not fully understand. The aim of this study was to investigate the cytotoxic effects of ouabain on human prostate cancer DU 145 cells in vitro. Cell morphological changes were examined by phase contrast microscopy. Cell viability, cell cycle distribution, cell apoptosis, DNA damage, the production of ROS and Ca²⁺, and mitochondrial membrane potential (ΔΨ_m) were measured by flow cytometry assay. Results indicated that ouabain induced cell morphological changes, decreased total cell viability, induced G0/G1 phase arrest, DNA damage, and cell apoptosis, increased ROS and Ca²⁺ production, but decreased the levels of ΔΨ_m in DU 145 cells. Ouabain also increased the activities of caspase‐3, ‐8, and ‐9. Western blotting was used for measuring the alterations of apoptosis‐associated protein expressions in DU 145 cells and results indicated that ouabain increased the expression of DNA damage associated proteins (pATM^Ser1981, p‐H2A.X^Ser139, and p‐p53^Ser15) and ER‐stress‐associated proteins (Grp78, ATF6β, p‐PERK^Thr981, PERK, eIF2A, GADD153, CaMKIIβ, and caspase‐4) in time‐dependently. Furthermore, ouabain increased apoptosis‐associated proteins (DR4, DR5, Fas, Fas Ligand, and FADD), TRAIL pathway, which related to extrinsic pathway, promoted the pro‐apoptotic protein Bax, increased apoptotic‐associated proteins, such as cytochrome c, AIF, Endo G, caspase‐3, ‐8, and ‐9, but reduced anti‐apoptotic protein Bcl‐2 and Bcl‐x in DU 145 cells. In conclusion, we may suggest that ouabain decreased cell viability and induced apoptotic cell death may via caspase‐dependent and mitochondria‐dependent pathways in human prostate cancer DU 145 cells.     

3‐Aminomethyl pyridine chalcone derivatives: Design,synthesis, DNA binding and cytotoxic studies

Herein we report design, synthesis, and anticancer activity of compounds 6a–h and 11a–j . Compounds 6a–f were designed based on 3‐aminomethyl pyridine attached to different acetamide derivatives and in compounds 6g–h it was attached to coumarin moiety. Coumarin containing compounds 6g–h showed very poor anticancer activity against both A549 (Lungs cancer cell line), and MCF‐7 (Breast cancer cell line) cell lines in MTT assay. Compounds 11a–j were designed as derivatives of 3‐aminomethyl pyridine and 4‐amino chalcones. A series of chalcone derivatives of 3‐aminomethyl pyridine 11a–j have been synthesized and screened for their in vitro anticancer activity and DNA binding affinity. Most of the compounds showed very good antimitotic activity against A549 cell line as compared to fluorouracil. Compounds 11g and 11i were selected for DNA‐binding studies as they showed excellent activity against cancer cell lines in MTT assay. CT‐DNA binding affinity of compounds 11g and 11i have been investigated by UV based DNA titration and fluorescence emission study against DNA‐EtBr complex. Interestingly, compound 11i has displayed excellent antiproliferative activity, with IC₅₀ 0.0067 ± 0.0002 μm , against MCF‐7 cell line. Compound 11i has been studied for its cytotoxicity using MTT, LDH, as well as EtBr/AO assay and was found to induce apoptosis in the cancerous cell line.     

Crude extract of Rheum palmatum L induced cell death in LS1034 human colon cancer cells acts through the caspase‐dependent and ‐independent pathways

Crude extract of Rheum palmatum L (CERP) has been used to treat different diseases in the Chinese population for decades. In this study, we investigated the effects of CERP on LS1034 human colorectal cancer cells in vitro and also examined possible mechanisms of cell death. Flow cytometric assays were used to measure the percentage of viable cells, cell cycle distribution including the sub‐G1 phase (apoptosis), the activities of caspase‐8, ‐9, and ‐3, reactive oxygen species (ROS) and Ca²⁺ levels, and mitochondrial membrane potential (ΔΨ_m). DNA damage, nuclei condensation, protein expression, and translocation were examined by Comet assay, 4′‐6‐diamidino‐2‐phenylindole (DAPI) staining, Western blotting, and confocal laser system microscope, respectively. CERP induced apoptosis as seen by DNA fragmentation and DAPI staining in a concentration‐ and time‐dependent manner in cancer cells. CERP was associated with an increase in the Bax/Bcl‐2 protein ratio and CERP promoted the activities of caspase‐8, ‐9, and ‐3. Both ROS and Ca²⁺ levels were increased by CERP but the compound decreased levels of ΔΨ_m in LS1034 cells. Laser confocal microscope also confirmed that CERP promoted the expressions of AIF, Endo G, cytochrome c, and GADD153 to induce apoptosis through mitochondrial‐dependent pathway. © 2013 Wiley Periodicals, Inc. Environ Toxicol 29: 969–980, 2014.     

Discovery and antiproliferative evaluation of new quinoxalines as potential DNA intercalators and topoisomerase II inhibitors

In continuation of our previous work on the design and synthesis of topoisomerase II (Topo II) inhibitors and DNA intercalators, a new series of quinoxaline derivatives were designed and synthesized. The synthesized compounds were evaluated for their cytotoxic activities against a panel of three cancer cell lines (Hep G‐2, Hep‐2, and Caco‐2). Compounds 18b, 19b, 23, 25b , and 26 showed strong potencies against all tested cell lines with IC₅₀ values ranging from 0.26 ± 0.1 to 2.91 ± 0.1 µM, comparable with those of doxorubicin (IC₅₀ values ranging from 0.65 ± 0.1 to 0.81 ± 0.1 µM). The most active compounds were further evaluated for their Topo II inhibitory activities and DNA intercalating affinities. Compounds 19b and 19c exhibited high activities against Topo II (IC₅₀ = 0.97 ± 0.1 and 1.10 ± 0.1 µM, respectively) and bound the DNA at concentrations of 43.51 ± 2.0 and 49.11 ± 1.8 µM, respectively, whereas compound 28b exhibited a significant affinity to bind the DNA with an IC₅₀ value of 37.06 ± 1.8 µM. Moreover, apoptosis and cell‐cycle tests of the most promising compound 19b were carried out. It was found that 19b can significantly induce apoptosis in Hep G‐2 cells. It has revealed cell‐cycle arrest at the G2/M phase. Moreover, compound 19b downregulated the Bcl‐2 levels, indicating its potential to enhance apoptosis. Furthermore, molecular docking studies were carried out against the DNA–Topo II complex to examine the binding patterns of the synthesized compounds.     

A Cisplatin Derivative that Inhibits Collagen Fibril‐Formation in vitro

Using an in vitro random screening of small‐molecule compounds, we discovered cis‐diamminedichloroplatinum(II) (cisplatin), an anticancer agent, as a potential inhibitor of collagen fibril‐formation. The inhibitory effect was found only when cisplatin was dissolved in dimethylsulphoxide (DMSO), indicating that the active species were cisplatin derivatives formed in the DMSO solution. The cisplatin derivatives inhibited the formation of collagen fibrils in vitro without affecting the triple‐helical conformation of the collagen molecules. Incubation with the cisplatin solution in DMSO also inhibited in situ deposition of collagen fibrils in a human umbilical vein endothelial cell (HUVEC) culture. In addition, the derivatization of cisplatin in DMSO abolished the cytotoxicity of the original compound. The platinum complex was further revealed to interact with specific sites on the collagen triple helix, and the binding sites were suggested to contain His and/or Met residues. Mass spectrometry analysis of the cisplatin solution in DMSO and a structure–activity relationship study strongly suggested that the active compound is [Pt(NH₃)₂(Cl)(DMSO)]⁺. This platinum complex will be useful for investigating molecular mechanisms of collagen self‐assembly and for drug development for the treatment of fibrotic diseases.     

Bufalin induces apoptosis in vitro and has Antitumor activity against human lung cancer xenografts in vivo

Bufalin has been shown to be effective against a variety of cancer cells, but its role in lung cancer has never been studied in an animal model. In this study, we evaluated bufalin effects in a human lung cancer cell line NCI‐H460 both in vitro and in vivo . Bufalin caused significant cytotoxicity in NCI‐H460 cells at a concentration as low as 1 μM. DNA condensation was observed in bufalin‐treated cells in a dose‐dependent manner. Mitochondrial membrane potential (ΔΨ_m) was reduced and reactive oxygen species (ROS) were increased in bufalin‐treated NCI‐H460 cells. Levels of several proapoptotic proteins such as Fas, Fas‐ligand, cytochrome c , apoptosis protease activating factor‐1, endonuclease G, caspase‐3 and caspase‐9 were increased after bufalin treatment. At the same time, anti‐apoptotic B‐cell lymphoma 2 protein levels were reduced. Bufalin decreased glucose regulated protein‐78 gene expression but increased growth arrest‐ and DNA damage‐inducible 153 gene expression. Bufalin injected intraperitoneally in a dose‐dependent manner reduced tumor size in BALB/C nu/nu mice implanted with NCI‐H460 cells. Bufalin injection did not produce significant drug‐related toxicity in experimental animals except at a high dose (0.4 mg kg^?1). In conclusion, low concentrations of bufalin can induce apoptosis in the human lung cancer cell line NCI‐H460 in vitro . Bufalin also reduced tumor size in mice injected with NCI‐H460 cells without significant drug‐related toxicity. These results indicate that bufalin may have potential to be developed as an agent for treating human non‐small cell lung cancer. © 2016 Wiley Periodicals, Inc. Environ Toxicol 32: 1305–1317, 2017.     

Sodium perbarate and benzalkonium chloride induce DNA damage in Chang conjunctival epithelial cells

Content and objective: To investigate and compare the toxic effects of benzalkonium chloride (BAC) and new type oxidative preservative sodium perborate (NaBO₃) on DNA damage, reactive oxygen species (ROS), and cell survival in immortalized human Chang conjunctival cells.

Materials and methods: Cells were exposed to BAC and NaBO₃ in concentrations of 0.00001–0.001% for 30?min. Cell viability was measured by the MTT test. Alkaline comet assay was used to detect DNA damage. Mitochondrial membrane potential (MMP), cell apoptosis, and ROS production were detected by flow cytometry analysis.

Results: Significant changes in the relative cell survival rate in cells were observed after exposure to 0.0005–0.001% BAC for 30?min (p?p?3 did not induce the decrease in cell survival and MMP in low concentration but could induce DNA damage and ROS generation in a 0.001% concentration (p?Discussion and conclusions: BAC can induce DNA damage in human conjunctival epithelial cells; this effect may be related to oxidative stress. Although NaBO₃ did not induce a significant decrease in cell survival and MMP, DNA damage and ROS generation were still detected in high concentration. New type oxidative preservative has less toxicity than the old type, but it still has the tendency of producing genotoxic changes in an in vitro test system.     

Comparative effects of sulfhydryl compounds on target organellae,nuclei and mitochondria,of hydroxylated fullerene‐induced cytotoxicity in isolated rat hepatocytes

DNA damage and cytotoxicity induced by a hydroxylated fullerene [C₆₀(OH)₂₄], which is a spherical nanomaterial and/or a water‐soluble fullerene derivative, and their protection by sulfhydryl compounds were studied in freshly isolated rat hepatocytes. The exposure of hepatocytes to C₆₀(OH)₂₄ at a concentration of 50 μM caused time (0 to 3 h)‐dependent cell death accompanied by the formation of cell surface blebs, the loss of cellular levels of ATP and reduced glutathione, accumulation of glutathione disulfide, and induction of DNA fragmentation assayed using alkali single‐cell agarose‐gel electrophoresis. C₆₀(OH)₂₄‐induced cytotoxicity was effectively prevented by pretreatment with sulfhydryl compounds. N‐acetyl‐L‐cysteine (NAC), L‐cysteine and L‐methionine, at a concentration of 2.5 mM, ameliorated cell death, accompanied by a decrease in cellular ATP levels, formation of cell surface blebs, induction of reactive oxygen species (ROS) and loss of mitochondrial membrane potential caused by C₆₀(OH)₂₄. In addition, DNA fragmentation caused by C₆₀(OH)₂₄ was also inhibited by NAC, whereas an antioxidant ascorbic acid did not affect C₆₀(OH)₂₄‐induced cell death and DNA damage in rat hepatocytes. Taken collectively, these results indicate that incubation of rat hepatocytes with C₆₀(OH)₂₄ elicits DNA damage, suggesting that nuclei as well as mitochondria are target sites of the hydroxylated fullerene; and induction of DNA damage and oxidative stress is ameliorated by an increase in cellular GSH levels, suggesting that the onset of toxic effects may be partially attributable to a thiol redox‐state imbalance caused by C₆₀(OH)₂₄. Copyright © 2015 John Wiley & Sons, Ltd.     

Oleanolic acid arrests cell cycle and induces apoptosis via ROS‐mediated mitochondrial depolarization and lysosomal membrane permeabilization in human pancreatic cancer cells

Oleanolic acid (OA), a pentacyclic triterpenoid, exhibits potential anti‐tumor activity against many tumor cell lines. This study aims to examine the anti‐tumor activity of OA on pancreatic cancer cells and its potential molecular mechanism. The results showed that the proliferation of Panc‐28 cells was inhibited by OA in a concentration‐dependent manner, with an IC₅₀ (The half maximal inhibitory concentration) value of 46.35 µg ml^?1, as determined by MTT (3‐(4,5‐Dimethylthiazol‐2‐yl)‐2,5‐diphenyltetrazolium bromide) assay. The cell cycle was arrested in S phase and G2/M phase by OA. The study also showed that OA could induce remarkable apoptosis, evidenced by an increased percentage of early/late apoptotic cells, DNA ladder and nuclear morphology change. Further study revealed that OA could induce Reactive Oxygen Species (ROS) generation, mitochondrial depolarization, release of cytochrome C, lysosomal membrane permeabilization and leakage of cathepin B. The expression of apoptosis‐correlated proteins was also affected in cells treated with OA, including activation of caspases‐3/9 and cleavage of PARP. Further study confirmed that ROS scavenger vitamin C could reverse the apoptosis induced by OA in Panc‐28 cells. Our results provide evidence that OA arrests the cell cycle and induces apoptosis, possibly via ROS‐mediated mitochondrial and a lysosomal pathway in Panc‐28 cells. Copyright © 2012 John Wiley & Sons, Ltd.     

Antagonistic effect of N‐ethylmaleimide on arsenic‐mediated oxidative stress‐induced poly(ADP‐ribosyl)ation and cytotoxicity

Long‐term exposure to arsenic has been known to induce neoplastic initiation and progression in several organs; however, the role of arsenic (As₂O₃) in oxidative stress‐mediated DNA damage remains elusive. One of the immediate cellular responses to DNA damage is poly(ADP‐ribosyl)ation (PARylation), which mediates DNA repair and enhances cell survival. In this study, we found that oxidative stress (H₂O₂)‐induced PARylation was suppressed by As₂O₃ exposure in different human cancer cells. Moreover, As₂O₃ treatment promoted H₂O₂‐induced DNA damage and apoptosis, leading to increased cell death. We found that N‐ethylmaleimide (NEM), an organic compound derived from maleic acid, could reverse As₂O₃‐mediated effects, thus enhancing PARylation with attenuated cell death and increased cell survival. Pharmacologic inhibition of glutathione with l ‐buthionine‐sulfoximine blocked the antagonistic effect of NEM on As₂O₃, thereby continuing As₂O₃‐mediated suppression of PARylation and causing DNA damage. Our findings identify NEM as a potential antidote against As₂O₃‐mediated DNA damage in a glutathione‐dependent manner. Copyright © 2016 John Wiley & Sons, Ltd.     

Synthesis,molecular docking and biological evaluation of 1‐phenylsulphonyl‐2‐(1‐methylindol‐3‐yl)‐benzimidazole derivatives as novel potential tubulin assembling inhibitors

A series of new 1‐phenylsulphonyl‐2‐(1‐methylindol‐3‐yl)‐benzimidazole derivatives were designed, synthesized and evaluated as potential inhibitors of tubulin polymerization and anthropic cancer cell lines. Among them, compound 33 displayed the most potent tubulin polymerization inhibitory activity in vitro (IC₅₀ = 1.41 μM) and strong antiproliferative activities against A549, Hela, HepG2 and MCF‐7 cell lines in vitro with GI₅₀ value of 1.6, 2.7, 2.9 and 4.3 μM, respectively, comparable with the positive control colchicine (GI₅₀ value of 4.1, 7.2, 9.5 and 14.5 μM, respectively) and CA‐4 (GI₅₀ value of 2.2, 4.3, 6.4 and 11.4 μM, respectively). Simultaneously, we evaluated that compound 33 could effectively induce apoptosis of A549 associated with G2/M phase cell cycle arrest. Immunofluorescence microscopy also clearly indicated compound 33 a potent antimicrotubule agent. Docking simulation showed that compound 33 could bind tightly with the colchicine‐binding site and act as a tubulin inhibitor. Three‐dimensional‐QSAR model was also built to provide more pharmacophore understanding that could be used to design new agents with more potent tubulin assembling inhibitory activity in the future.     

Tetrandrine inhibits human brain glioblastoma multiforme GBM 8401 cancer cell migration and invasion in vitro

Tetrandrine (TET) has been reported to induce anti‐cancer activity in many human cancer cells and also to inhibit cancer cell migration and invasion. However, there are no reports to show TET inhibits cell migration and invasion in human brain glioblastoma multiforme GBM 8401 cells. In this study, we investigated the anti‐metastasis effects of TET on GBM 8401 cells in vitro. Under sub‐lethal concentrations (from 1, 5 up to 10 μM), TET significantly inhibited cell mobility, migration and invasion of GBM 8401 cells that were assayed by wound healing and Transwell assays. Gelatin zymography assay showed that TET inhibited MMP‐2 activity in GBM 8401 cells. Western blotting results indicated that TET inhibited several key metastasis‐related proteins, such as p‐EGFR_(Tyr1068), SOS‐1, GRB2, Ras, p‐AKT_(Ser473) and p‐AKT_(Thr308), NF‐κB‐p65, Snail, E‐cadherin, N‐cadherin, NF‐κB, MMP‐2 and MMP‐9 that were significant reduction at 24 and 48 hours treatment by TET. TET reduced MAPK signaling associated proteins such as p‐JNK1/2 and p‐c‐Jun in GBM 8401 cells. The electrophoretic mobility shift (EMSA) assay was used to investigate NF‐κB and DNA binding was reduced by TET in a dose‐dependently. Based on these findings, we suggested that TET could be used in anti‐metastasis of human brain glioblastoma multiforme GBM 8401 cells in the future.     

Casticin impairs cell growth and induces cell apoptosis via cell cycle arrest in human oral cancer SCC‐4 cells

Casticin, a polymethoxyflavone, present in natural plants, has been shown to have biological activities including anti‐cancer activities. Herein, we investigated the anti‐oral cancer activity of casticin on SCC‐4 cells in vitro. Viable cells, cell cycle distribution, apoptotic cell death, reactive oxygen species (ROS) production, and Ca²⁺ production, levels of ΔΨ_m and caspase activity were measured by flow cytometric assay. Cell apoptosis associated protein expressions were examined by Western blotting and confocal laser microscopy. Results indicated that casticin induced cell morphological changes, DNA condensation and damage, decreased the total viable cells, induced G₂/M phase arrest in SCC‐4 cells. Casticin promoted ROS and Ca²⁺ productions, decreases the levels of ΔΨ_m, promoted caspase‐3, ‐8, and ‐9 activities in SCC‐4 cells. Western blotting assay demonstrated that casticin affect protein level associated with G2/M phase arrest and apoptosis. Confocal laser microscopy also confirmed that casticin increased the translocation of AIF and cytochrome c in SCC‐4 cells. In conclusion, casticin decreased cell number through G₂/M phase arrest and the induction of cell apoptosis through caspase‐ and mitochondria‐dependent pathways in SCC‐4 cells.     

In vitro evaluation of apoptotic effect of bis(acetylacetonato‐k2 O,O′)(1,10‐phenanthroline‐k2 N,N′)Zn(II) complex

Phenanthroline derivatives have been reported as potential bioactive compounds because of their ability to interact with DNA . To evaluate the antiproliferative effect of bis (acetylacetonate‐k ² O,O )(1,10‐phenanthroline‐k ² N,N )Zn(II ) or Zn(acac)₂(phen) complex, the compound was obtained in a simple manner and further characterized to determine crystal structure, thermal behavior, morphology, and spectroscopic properties. The structure of the complex was confirmed by X‐ray single structure as well as by 1H and 13C nuclear magnetic resonance (NMR ) in dmso‐d6 (dimethyl sulfoxide) solution and in the solid state by 13C CP /MAS . Although preparation of this compound has been described previously, there are no reports on its biological activity; here, we assessed its antiproliferative effect on fibroblasts, A253, FaDu, Cal‐27, RH ‐30, RD , U‐373, C6, A‐549, MDA ‐MB ‐231, and MCF ‐7 cancer cell lines at different doses (50–100 and 150 μg/ml). The cell viability was determined by MTT assay and high activity was observed for the most of the cell lines, and TUNEL results showed the induction of apoptosis.     

Aflatoxin G1-induced oxidative stress causes DNA damage and triggers apoptosis through MAPK signaling pathway in A549 cells

Our previous studies showed that Aflatoxin G₁ (AFG₁) could induce lung adenocarcinoma, and that the cancer cells originated from alveolar type II cells (AT-II cells). Recently, we found AFG₁ induced structural impairment in rat AT-II cells, which may account for an early event in lung tumorigenesis. However, the mechanism of AFG₁-induced AT-II cell damage remains unclear. DNA damage and apoptosis induced by oxidative stress are well accepted causes of cell damage. Thus, we explore whether AFG₁ activates the reactive oxygen species (ROS)/MAPK/apoptosis pathway to cause cell damage in human AT-II cells like the cell line (A549). We found AFG₁ induced oxidative stress by increasing ROS generation and caused DNA double-strand breaks (DSBs) by up-regulating γH2AX expression. AFG₁ also triggered apoptosis in A549 cells by regulating Fas/FasL, caspase-8, Bax, Bcl-2, and activating caspase-3. Pre-treatment with antioxidant n-acetyl-l-cysteine (NAC) reduced ROS generation and DNA DSBs, inhibited apoptosis, and increased cell viability in AFG₁-treated cells. Furthermore, we found AFG₁ activated ROS-mediated JNK and p38 pathways to induce cell apoptosis in A549 cells. In conclusion, our results indicate that AFG₁ induces oxidative DNA damage and triggers apoptosis through ROS-mediated JNK and p38 signaling pathways in A549 cells, which may contribute to AFG₁-induced AT-II cell damage.     

Effect of polyethylene glycol surface charge functionalization of SWCNT on the in vitro and in vivo nanotoxicity and biodistribution monitored noninvasively using MRI

The current study evaluated in vitro and in vivo toxicity of carboxyl or amine polyethylene glycol (PEG) surface functionalization of single-walled carbon nanotubes (SWCNTs). Assessments of cytotoxicity, genotoxicity, immunotoxicity, and oxidative stress were performed in vitro and in vivo (in a 1-month follow-up study). The SWCNT biodistribution was investigated using noninvasive magnetic resonance imaging (MRI). Results confirmed the enhanced biocompatibility of PEG-functionalized SWCNTs compared to non-functionalized materials with significant decreases (p?p?2 functionalized SWCNTs after 2 weeks’ exposure. The negatively charged SWCNTs caused lesser DNA damage compared to positively charged samples. Carboxy-functionalized SWCNTs did not cause substantial changes in inflammatory mediators and were found to be significantly safer than non-functionalized SWCNTs and may pave the way for novel biomedical applications in cancer diagnosis and therapy.     

Protection of coronary endothelial cells from cigarette smoke-induced oxidative stress by a new MnII-containing polyamine-polycarboxilate scavenger of superoxide anion

Oxidative stress plays a major role in cardiovascular injury and dysfunction induced by cigarette smoke. Smoke-borne pro-oxidants impair endothelial function and predispose to thrombosis, inflammation and atherosclerosis. This in vitro study evaluates whether Mn^II(4,10-dimethyl-1,4,7,10-tetraazacyclododecane-1,7-diacetate).2H₂O (Mn^II(Me₂DO2A)), a polyamine–polycarboxilate, Mn^II-containing O₂⁻ scavenger, has a direct protective action on guinea pig coronary endothelial (GPCE) cells exposed to cigarette smoke extracts (CSE).Mn^II(Me₂DO2A) (1–10 μmol/l) was added to the culture medium together with CSE and maintained for 4 h. In parallel experiments, the inactive congener Zn^II(Me₂DO2A), in which Zn^II replaced the functional Mn^II center in the same organic scaffold, was used as negative control.Mn^II(Me₂DO2A), mostly at the higher doses (5 and 10 μmol/l), significantly increased GPCE cell viability (trypan blue assay), improved mitochondrial activity (MTT test, mitochondrial membrane potential Δψ), reduced cellular apoptosis (mPTP, caspase-3 activity, TUNEL assay), decreased intracellular ROS levels (H₂DCFDA), lipoperoxidation (BODIPY 581/591) and decreased protein nitrosylation. Of note, Zn^II(Me₂DO2A) did not preserve cell viability. These findings suggest that Mn^II(Me₂DO2A) is a promising O₂⁻ scavenging compound able to protect from cigarette smoke-induced oxidative cell injury. In perspective, should its efficacy be confirmed in future in vivo studies, this molecule might represent a therapeutic or preventive drug to counteract cigarette smoke toxicity.     

Structure Effect of Some New Anticancer Pt(II) Complexes of Amino Acid Derivatives with Small Branched or Linear Hydrocarbon Chains on Their DNA Interaction

The aim of this study was to investigate the structure effect and identify the modes of binding of amino acid‐Pt complexes to DNA molecule for cancer treatment. Hence, three novel water soluble platinum complexes, [Pt(phen)(R‐gly)]NO₃ (where phen is 1,10‐phenanthroline, R‐gly is methyl, amyl, and isopentyl‐glycine), have been synthesized and characterized by spectroscopic methods, conductivity measurements, and chemical analysis. The anticancer activities of synthesized complexes were investigated against human breast cancer cell line of MDA‐MB 231. The 50% cytotoxic concentration values were determined to be 42.5, 58, and 70 μm for methyl‐, amyl‐, and isopentyl‐gly complexes, respectively. These complexes were interacted with calf thymus DNA (ct‐DNA) via positive cooperative interaction. The modes of binding of the complexes to DNA were investigated by fluorescence spectroscopy and circular dichroism in combination with a molecular docking study. The result indicates that complexes with small or branched hydrocarbon chains can intercalate with DNA. This is while amyl complexes with linear chains interacted additionally via groove binding. The results of the negative value of Gibbs energy for binding of isopentyl‐platinum to DNA and those of the molecular docking were coherent. Furthermore, the docking results demonstrated that hydrophobic interaction plays an important role in the complex–DNA interaction.