Secosteroid-quinoline hybrids as new anticancer agents.

An elegant approach to unknown secosteroid-quinoline hybrids is disclosed. A series of 13,17-secoestra-1,3,5(10)-trien-17-oic acid [N'-(iso)quinolylmethylene]hydrazides was prepared and these novel type of secosteroids was screened for antiproliferative activity against estrogen-responsive human breast cancer cell line MCF-7. Most of the synthesized compounds showed a cytotoxic effect superior to that of reference drug cisplatin; the lead compound exhibits the highest activity with the IC50 value of about 0.8 µM and is 7 times more active than cisplatin. A high selectivity index was observed for the hit 13,17-secoestra-1,3,5(10)-trien-17-oic acid [N'-quinolylmethylene]hydrazides 2a and 2c. Compounds 2a and 2c evaluated in luciferase reporter assays exhibited high antiestrogenic potency which was superior to that of tamoxifen. These hit compounds were characterized by high activity against MCF-7 cells that retained towards multidrug-resistant NCI/ADR-RES cells.

AKT-driven epithelial-mesenchymal transition is affected by copper bioavailability in HER2 negative breast cancer cells via a LOXL2-independent mechanism.

BACKGROUND: The main mechanism underlying cancer dissemination is the epithelial to mesenchymal transition (EMT). This process is orchestrated by cytokines like TGFß, involving "non-canonical" AKT- or STAT3-driven pathways. Recently, the alteration of copper homeostasis seems involved in the onset and progression of cancer. METHODS: We expose different breast cancer cell lines, including two triple negative (TNBC) ones, an HER2 enriched and one cell line representative of the Luminal A molecular subtype, to short- or long-term copper-chelation by triethylenetetramine (TRIEN). We analyse changes in the expression of EMT markers (E-cadherin, fibronectin, vimentin and αSMA), in the levels and activity of extracellular matrix components (LOXL2, fibronectin and MMP2/9) and of copper homeostasis markers by Western blot analyses, immunofluorescence, enzyme activity assays and RT-qPCR. Boyden Chamber and wound healing assays revealed the impact of copper chelation on cell migration. Additionally, we explored whether perturbation of copper homeostasis affects EMT prompted by TGFß. Metabolomic and lipidomic analyses were applied to search the effects of copper chelation on the metabolism of breast cancer cells. Finally, bioinformatics analysis of data on breast cancer patients obtained from different databases was employed to correlate changes in kinases and copper markers with patients' survival. RESULTS: Remarkably, only HER2 negative breast cancer cells differently responded to short- or long-term exposure to TRIEN, initially becoming more aggressive but, upon prolonged exposure, retrieving epithelial features, reducing their invasiveness. This phenomenon may be related to the different impact of the short and prolonged activation of the AKT kinase and to the repression of STAT3 signalling. Bioinformatics analyses confirmed the positive correlation of breast cancer patients' survival with AKT activation and up-regulation of CCS. Eventually, metabolomics studies demonstrate a prevalence of glycolysis over mitochondrial energetic metabolism and of lipidome changes in TNBC cells upon TRIEN treatment. CONCLUSIONS: We provide evidence of a pivotal role of copper in AKT-driven EMT activation, acting independently of HER2 in TNBC cells and via a profound change in their metabolism. Our results support the use of copper-chelators as an adjuvant therapeutic strategy for TNBC.

N,N'-1,10-Bis(Naringin) Triethylenetetraamine, Synthesis and as a Cu(II) Chelator for Alzheimer's Disease Therapy.

The bis-Schiff base of N,N'-1,10-bis(naringin) triethylenetetraamine (1) was prepared, as a copper(II) ion chelator, compound 1 was used for Alzheimer's disease therapy in vitro. The 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay of compound 1 showed that this Schiff base could promote PC12 cells proliferation, and also, compound 1 could inhibit Cu2+-amyloid-ß (Aß)1-42 mediated cytotoxicity on PC12 cells. The thioflavine T (ThT) assay showed that 1 can effectively attenuate Cu2+-induced Aß1-42 aggregation. In addition, compound 1 is determined to be potent antioxidants on the basis of in vitro antioxidant assay, it can effectively decease the level of reactive oxygen species (ROS) in Cu2+-Aß1-42-treated PC12 cells and elevate the superoxide dismutase (SOD) activity in Cu2+-Aß1-42-treated PC12 cells. The results show that N,N'-1,10-bis(naringin) triethylenetetraamine is a potential agent for therapy of Alzheimer's disease.

Octahedral copper(ii)-diimine complexes of triethylenetetramine: effect of stereochemical fluxionality and ligand hydrophobicity on CuII/CuI redox, DNA binding and cleavage, cytotoxicity and apoptosis-inducing ability.

Octahedral copper(ii) complexes of the type [Cu(trien)(diimine)](ClO4)2 (1-4), where trien is triethylenetetramine and diimine is 2,2'-bipyridine (1), 1,10-phenanthroline (2), 5,6-dimethyl-1,10-phenanthroline (3), and 3,4,7,8-tetramethyl-1,10-phenanthroline (4), have been isolated. Single crystal X-ray structures of 1 and 2 reveal that the coordination geometry around Cu(ii) is tetragonally distorted octahedral. The stereochemical fluxionality of the complexes illustrates the observed trend in CuII/CuI redox potentials and DNA binding affinity (Kb: 1, 0.030 ± 0.002 < 2, 0.66 ± 0.01 < 3, 1.63 ± 0.10 < 4, 2.27± 0.20 × 105 M-1), determined using absorption spectral titration. All complexes effect oxidative DNA cleavage more efficiently than hydrolytic DNA cleavage. The bpy complex 1 with stereochemical fluxionality lower than its phen analogue 2 shows a higher cytotoxicity against both A549 lung (IC50, 3.3 µM) and MCF-7 human breast (IC50, 3.9 µM) cancer cells, and induces the generation of the highest amount of ROS in A549 cells. Complex 3 with a higher stereochemical fluxionality and higher ligand hydrophobicity exhibits a higher DNA binding and cleavage ability and higher cytotoxicity (IC50, 2.1 µM) towards MCF-7 cells. Complex 4 with a still higher stereochemical fluxionality displays the highest DNA binding and cleavage ability but a lower cytotoxicity towards both A549 and MCF-7 cell lines due to its tendency to form a five-coordinated complex with the uncoordinated amine group. Annexin V.Cy3 staining and immunoblot analysis demonstrate the mechanism of cell death caused by 1 and 2. The finding of the up-regulation of the pro-apoptotic Bax protein and down-regulation of PARP protein in western blot analysis confirms the induction of apoptosis by these complexes.

Stereoselective synthesis of the four 16-hydroxymethyl-3-methoxy- and 16-hydroxymethyl-3-benzyloxy-13α-estra-1,3,5(10)-trien-17-ol isomers and their antiproliferative activities.

The reduction of 16-hydroxymethylene-3-methoxy-13α-estra-1,3,5(10)-trien-17-one (14) and 16-hydroxymethylene-3-benzyloxy-13α-estra-1,3,5(10)-trien-17-one (16) yielded a mixture of two diastereomeric diols, the 16α-hydroxymethyl,17ß-hydroxy and 16ß-hydroxymethyl,17α-hydroxy isomers (17a-20a) in a ratio of 6:1. We describe a straightforward synthetic route to transform the isomers with trans functional groups attached to ring D (17a-20a) into isomers with cis functional groups (25a-28a). We determined the in vitro antiproliferative activities of compounds 17a-20a and 25a-28a by means of MTT assays against a panel of human adherent cancer cell lines HeLa, A2780, MCF-7, T47D, MDA-MB-231 and MDA-MB-361.

Structure-activity relationship studies of 1,7-diheteroarylhepta-1,4,6-trien-3-ones with two different terminal rings in prostate epithelial cell models.

To systematically investigate the structure-activity relationships of 1,7-diheteroarylhepta-1,4,6-trien-3-ones in three human prostate cancer cell models and one human prostate non-neoplastic epithelial cell model, thirty five 1,7-diarylhepta-1,4,6-trien-3-ones with different terminal heteroaromatic rings have been designed for evaluation of their anti-proliferative potency in vitro. These target compounds have been successfully synthesized through two sequential Horner-Wadsworth-Emmons reactions starting from the appropriate aldehydes and tetraethyl (2-oxopropane-1,3-diyl)bis(phosphonate). Their anti-proliferative potency against PC-3, DU-145 and LNCaP human prostate cancer cell lines can be significantly enhanced by the manipulation of the terminal heteroaromatic rings, further demonstrating the utility of 1,7-diarylhepta-1,4,6-trien-3-one as a potential scaffold for the development of anti-prostate cancer agents. The optimal analog 40 is 82-, 67-, and 39-fold more potent than curcumin toward the three prostate cancer cell lines, respectively. The experimental data also reveal that the trienones with two different terminal aromatic rings possess greater potency toward three prostate cancer cell lines, but also have greater capability of suppressing the proliferation of PWR-1E benign human prostate epithelial cells, as compared to the corresponding counterparts with two identical terminal rings and curcumin. The terminal aromatic rings also affect the cell apoptosis perturbation.

Triethylenetetramine Synergizes with Pharmacologic Ascorbic Acid in Hydrogen Peroxide Mediated Selective Toxicity to Breast Cancer Cell.

Breast cancer is characterized by overexpression of superoxide dismutase (SOD) and downregulation of catalase and more resistance to hydrogen peroxide (H2O2) than normal cells. Thus, relatively high H2O2 promotes breast cancer cell growth and proliferation. However, excessive intracellular H2O2 leads to death of breast cancer cells. In cancer cells, high level ascorbic acid (Asc) is able to be autoxidized and thus provides an electron to oxygen to generate H2O2. In the present study, we demonstrated that triethylenetetramine (TETA) enhances Asc autoxidation and thus elevates H2O2 production in MCF-7 cells. Furthermore, Asc/TETA combination significantly impaired cancer cell viability, while having much milder effects on normal cells, indicating Asc/TETA could be a promising therapy for breast cancer. Moreover, SOD1 and N-acetyl-L-cysteine failed to improve MCF-7 cells viability in the presence of Asc/TETA, while catalase significantly inhibited the cytotoxicity of Asc/TETA to breast cancer cells, strongly suggesting that the selective cytotoxicity of Asc/TETA to cancer cells is H2O2-dependent. In addition, Asc/TETA induces RAS/ERK downregulation in breast cancer cells. Animal studies confirmed that Asc/TETA effectively suppressed tumor growth in vivo. In conclusion, TETA synergizes pharmacologic Asc autoxidation and H2O2 overproduction in breast cancer cells, which suppresses RAS/ERK pathway and results in apoptosis.

Copper chelation by trientine dihydrochloride inhibits liver RFA-induced inflammatory responses in vivo.

OBJECTIVE: Hepatocellular carcinoma (HCC) is the fifth most common cancer and the third most common cause of cancer-related death worldwide. Radiofrequency ablation (RFA) is currently performed widely for managing HCC. RFA treatment causes damage around the ablation. Trientine dihydrochloride has been used to reduce the copper in liver. METHODS: The rats were treated with trientine dihydrochloride for 5 days before liver RFA. Liver function, copper concentration, inflammation biomarkers and MDA, SOD were analyzed after RFA treatment for 2 h, 2 and 5 days. RESULTS: The results indicated that trientine dihydrochloride reduced the copper in plasma and liver tissue significantly. And trientine dihydrochloride significantly inhibited RFA-induced inflammatory gene expression in liver. Similar inhibitory effects of trientine dihydrochloride were observed on ROS-induced malondialdehyde production in liver tissues. CONCLUSION: These results suggest that pre-treatment with the selective copper chelator trientine dihydrochloride can inhibit inflammatory response effectively during and after liver RFA in vivo. Chelation of copper to a lower level before liver RFA may be a novel strategy to prevent or ameliorate inflammatory responses in liver induced by RFA and to protect the parenchyma tissues in liver during and after RFA in HCC patients.

Triethylenetetramine modulates polyamine and energy metabolism and inhibits cancer cell proliferation.

Polyamine metabolism is an attractive anticancer drug target, since polyamines are absolutely required for cellular proliferation, and increased levels of polyamines and their biosynthetic enzyme ornithine decarboxylase (ODC) are associated with cancer. Triethylenetetramine (TETA) is a charge-deficient isosteric analogue of the polyamine spermidine (Spd) and a Cu(II)-chelating compound used for the treatment of Wilson's disease, and it has been implicated as a potential anticancer therapeutic drug. In the present study, we studied the effects of TETA in comparison with two other Cu(II)-chelators, D-penicillamine (PA) and tetrathiomolybdate (TTM), on polyamine metabolism in DU145 prostate carcinoma, MCF-7 breast carcinoma and JEG-3 choriocarcinoma cells. TETA induced antizyme, down-regulated ODC and inhibited [(14)C] Spd uptake. Moreover, it completely prevented α-difluoromethylornithine (DFMO)-induced increase in [(14)C] Spd uptake, and inhibited [(14)C] putrescine (Put) uptake and ODC activity in vivo Seven-day treatment of DU145 cells with TETA caused growth cessation by reducing intracellular polyamine levels and suppressing the formation of hypusinated eukaryotic translation initiation factor 5A (eIF5A). TETA or its N-acetylated metabolites also inhibited spermine (Spm), diamine and semicarbazide-sensitive amine oxidases and decreased the level of intracellular reactive oxygen species. Moreover, TETA inhibited the utilization of Put as energy source via the tricarboxylic acid (TCA) cycle, as indicated by decreased production of (14)CO2 from [(14)C] Put. These results indicate that TETA attacks multiple proven anticancer drug targets not attributed to copper chelation, which warrants further studies to reveal its potential in cancer chemoprevention and cure.

Synthesis and evaluation of 1,7-diheteroarylhepta-1,4,6-trien-3-ones as curcumin-based anticancer agents.

Thirty (1E,4E,6E)-1,7-diaryl-1,4,6-heptatrien-3-ones, featuring a central linear trienone linker and two identical nitrogen-containing heteroaromatic rings, were designed and synthesized as curcumin-based anticancer agents on the basis of their structural similarity to the enol-tautomer of curcumin, in addition to taking advantage of the possibly enhanced pharmacokinetic profiles contributed by the basic nitrogen-containing heteroaromatic rings. Their cytotoxicity and antiproliferative activity were evaluated towards both androgen-dependent and androgen-independent prostate cancer cell lines, as well as HeLa human cervical cancer cells. Among them, the ten most potent analogues are 5- to 36-fold more potent than curcumin in inhibiting cancer cell proliferation. The acquired structure-activity relationship data indicate (i) that (1E,4E,6E)-1,7-diaryl-1,4,6-heptatrien-3-ones represent a potential scaffold for development of curcumin-based agents with substantially improved cytotoxicity and anti-proliferative effect; and (ii) 1-alkyl-1H-imidazol-2-yl and 1-alkyl-1H-benzo[d]imidazole-2-yl serve as optimal heteroaromatic rings for increased in vitro potency of this scaffold. Two of most potent compounds displayed no apparent cytotoxicity toward MCF-10A normal mammary epithelial cells at 1 µM concentration. Treatment of PC-3 prostate cancer cells with the most potent compound led to appreciable cell cycle arrest at a G1/G0 phase and cell apoptosis induction.

Co-administration of trientine and flaxseed oil on oxidative stress, serum lipids and heart structure in diabetic rats.

The administration of flaxseed oil or flaxseed oil plus trientine in diabetic rats reduced triglyceride, very low density lipoprotein, and total cholesterol. Furthermore, the combined treatment significantly increased superoxide dismutase activity and attenuated serum Cu2+. The results suggest that the administration of flaxseed oil plus trientine is useful in controlling serum lipid abnormalities, oxidative stress, restoring heart structure, and reducing serum Cu2+ in diabetic rats.

Trientine reduces BACE1 activity and mitigates amyloidosis via the AGE/RAGE/NF-κB pathway in a transgenic mouse model of Alzheimer's disease.

AIMS: There is mounting evidence that the transition metal copper may play an important role in the pathophysiology of Alzheimer's disease (AD). Triethylene tetramine dihydrochloride (trientine), a CuII-selective chelator, is a commonly used treatment for Wilson's disease to decrease accumulated copper, and thereby decreases oxidative stress. In the present study, we evaluated the effects of a 3-month treatment course of trientine (Trien) on amyloidosis in 7-month-old ß-amyloid (Aß) precursor protein and presenilin-1 (APP/PS1) double transgenic (Tg) AD model mice. RESULTS: We observed that Trien reduced the level of advanced glycation end products (AGEs), and decreased Aß deposition and synapse loss in brain of APP/PS1 mice. Importantly, we found that Trien blocked the receptor for AGEs (RAGE), downregulated ß-site APP cleaving enzyme 1 (BACE1), inhibited amyloidogenic APP cleavage, and subsequently reduced Aß levels. In vitro, in SH-SY5Y cells overexpressing Swedish mutant APP, Trien-mediated downregulation of BACE1 occurred via inhibition of the NF-κB signaling pathway. INNOVATION: In this study, we demonstrated for the first time that Trien inhibited amyloidogenic pathway including targeting the downregulation of RAGE and NF-κB. CONCLUSION: Trien might mitigate amyloidosis in AD by inhibiting the RAGE/NF-κB/BACE1 pathway. Our study demonstrates that Trien may be a viable therapeutic strategy for the intervention and treatment of AD and other AD-like pathologies.

Comparative evaluation of small-molecule chemosensitizers in reversal of cisplatin resistance in ovarian cancer cells.

Cisplatin-resistance is one of the major challenges in the treatment of epithelial ovarian cancer. Small-molecule chemosensitizers provide a therapeutically feasible approach to overcome cisplatin resistance in ovarian cancer. However, proper selection of chemosensitizer is of prime importance owing to phenotypic differences in cisplatin-resistant ovarian cancers. The resistance reversal activity of chemosensitizers buthionine sulfoximine (BSO), triethylenetetramine (TETA), genistein, rapamycin and colchicine was investigated in various cisplatin-resistant ovarian cancer cells, 2008 C13, CP70 and OVCAR 8 using MTT assays. Cellular accumulation of cisplatin in the presence of chemosensitizers was analyzed by inductively-coupled plasma-mass spectroscopy (ICP-MS). Chemosensitizers exhibited resistance reversal activity in 2008 C13 and CP70 cells in the following order; colchicine> genistein>TETA> rapamycin ≥ BSO (p<0.05), which is in correlation with cellular accumulation of cisplatin. In conclusion, our study demonstrates that resistance reversal activity of chemosensitizers varies with phenotypic behavior of cisplatin-resistant ovarian cancer cells. Data from our study can be utilized to choose a specific chemosensitizer for individualized combination therapy for cisplatin-resistant ovarian cancer.

Role of the cellular prion protein in the neuron adaptation strategy to copper deficiency.

Copper transporter 1 (CTR1), cellular prion protein (PrP(C)), natural resistance-associated macrophage protein 2 (NRAMP2) and ATP7A proteins control the cell absorption and efflux of copper (Cu) ions in nervous tissues upon physiological conditions. Little is known about their regulation under reduced Cu availability, a condition underlying the onset of diffused neurodegenerative disorders. In this study, rat neuron-like cells were exposed to Cu starvation for 48 h. The activation of Caspase-3 enzymes and the impairment of Cu,Zn superoxide dismutase (Cu,Zn SOD) activity depicted the initiation of a pro-apoptotic program, preliminary to the appearance of the morphological signs of apoptosis. The transcriptional response related to Cu transport proteins has been investigated. Notably, PrP(C) transcript and protein levels were consistently elevated upon Cu deficiency. The CTR1 protein amount was stable, despite a two-fold increase in the transcript amount, meaning the activation of post-translational regulatory mechanisms. NRAMP2 and ATP7A expressions were unvaried. The up-regulated PrP(C) has been demonstrated to enhance the cell Cu uptake ability by about 50% with respect to the basal transport, and so sustain the Cu delivery to the Cu,Zn SOD cuproenzymes. Conclusively, the study suggests a pivotal role for PrP(C) in the cell adaptation to Cu limitation through a direct activity of ion uptake. In this view, the PrP(C) accumulation observed in several cancer cell lines could be interpreted as a molecular marker of cell Cu deficiency and a potential target of therapeutic interventions against disorders caused by metal imbalances.

Copper depletion increases the mitochondrial-associated SOD1 in neuronal cells.

The role of copper in the toxicity of mutant copper-dependent enzyme superoxide dismutase (SOD1) found in patients affected with the familial form of amyotrophic lateral sclerosis (fALS) is widely debated. Here we report that treatment of human neuroblastoma cells SH-SY5Y with a specific copper chelator, triethylene tetramine (Trien) induces the decrease of intracellular copper level, paralleled by decreased activity of SOD1. A comparable effect is observed in mouse NSC-34-derived cells, a motoneuronal model, transfected for the inducible expression of either wild-type or G93A mutant human SOD1, one of the mutations associated with fALS. In both cell types, the drop of SOD1 activity is not paralleled by the same extent of decrease in SOD1 protein content. This discrepancy can be explained by the occurrence of a fraction of copper-free SOD1 upon copper depletion, which is demonstrated by the partial recovery of the enzyme activity after the addition of copper sulphate to homogenates of SH-SY5Y cells. Furthermore, copper depletion produces the enrichment of the physiological mitochondrial fraction of SOD1 protein, in both cells models. However, increasing the fraction of mitochondrial, possibly copper-free, mutant human SOD1 does not further alter mitochondrial morphology in NSC-34-derived cells. Thus, copper deficiency is not a factor which may worsen mitochondrial damage, which is one of the earliest events in fALS associated with mutant SOD1.

Triethylenetetramine pharmacology and its clinical applications.

Triethylenetetramine (TETA), a Cu(II)-selective chelator, is commonly used for the treatment of Wilson's disease. Recently, it has been shown that TETA can be used in the treatment of cancer because it possesses telomerase inhibiting and anti-angiogenesis properties. Although TETA has been used in the treatment of Wilson's disease for decades, a comprehensive review on TETA pharmacology does not exist. TETA is poorly absorbed with a bioavailability of 8 to 30%. It is widely distributed in tissues with relatively high concentrations measured in liver, heart, and kidney. It is mainly metabolized via acetylation, and two major acetylated metabolites exist in human serum and urine. It is mainly excreted in urine as the unchanged parent drug and two acetylated metabolites. It has a relatively short half-life (2 to 4 hours) in humans. The most recent discoveries in TETA pharmacology show that the major pharmacokinetic parameters are not associated with the acetylation phenotype of N-acetyltransferase 2, the traditionally regarded drug acetylation enzyme, and the TETA-metabolizing enzyme is actually spermidine/spermine acetyltransferase. This review also covers the current preclinical and clinical application of TETA. A much needed overview and up-to-date information on TETA pharmacology is provided for clinicians or cancer researchers who intend to embark on cancer clinical trials using TETA or its close structural analogs.

Trientine, a copper-chelating agent, induced apoptosis in murine fibrosarcoma cells by activation of the p38 MAPK pathway.

We have reported that treatment with trientine, Cu-chelating agent, inhibits tumor growth in a murine transplantation model using fibrosarcoma and induces apoptosis in tumor cells in vivo and in vitro. When fibrosarcoma cells were treated with 10 mM trientine, the activities of p38 MAPK in treated cells were approximately 3-4 times higher than those in untreated cells. Proportions of cells in which apoptosis was induced by trientine increased in an incubation time-dependent manner from days 2 to 6. The proportions of apoptotic cells in the cells treated with trientine and SB203580, an inhibitor of p38 MAPK, were approximately 50% in those of cells treated with trientine alone. The present results showed that the p38 MAPK pathway may play an important role in induction of apoptosis in fibrosarcoma cells by trientine.

Targeting superoxide dismutase 1 to overcome cisplatin resistance in human ovarian cancer.

PURPOSE: Clinical drug resistance to platinum-based chemotherapy is considered a major impediment in the treatment of human ovarian cancer. Multiple pathways associated with drug resistance have been suggested by many previous studies. Over expression of several key proteins involved in DNA repair, drug transport, redox regulation, and apoptosis has been recently reported by our group using a global quantitative proteomic profiling approach. Superoxide dismutase 1 (SOD1) is one of these proteins consistently over-expressed in cisplatin-resistant ovarian cancer cells as compared to their sensitive counterparts, but its precise role in drug resistance is yet to be defined. METHOD: In the current study, we examined the role of SOD1 in drug resistance by inhibiting its redox activity in cisplatin-resistant ovarian cancer cells using a small-molecule inhibitor, triethylenetetramine (TETA). The effect of TETA was determined by the cell proliferation assay, clonogenic cell survival assay, and SOD1 activity assay. RESULTS: The inhibition of the SOD1 activity enhanced the cisplatin sensitivity in the resistant cells supporting the hypothesis that SOD1 is a key determinant of cisplatin resistance and is an exploitable target to overcome cisplatin drug resistance. CONCLUSION: SOD1 plays an important role in cisplatin resistance and modulation of its activity may overcome this resistance and ultimately lead to improved clinical outcomes.

Inflammation induced by photocoagulation laser is minimized by copper chelators.

The effect of trientine hydrochloride (TRIEN), a copper-selective chelating agent, on retinal inflammation induced by photocoagulation laser treatment was studied. Nine Long-Evans rats were treated with TRIEN (0.5 mmol/kg per day, intraperitoneal injection) for 9 days. On day 8, each animal underwent unilateral photocoagulation laser treatment with an argon dye laser. On day 9, animals were killed and the eyes processed for immunohistochemistry and light microscopy. In the TRIEN-treated group, retinal thickness and number of macrophages (ED-1) were both significantly lower than in the saline-treated, control group exposed to laser photocoagulation. The results support the hypothesis that selective copper chelation prior to laser treatment may inhibit ocular inflammation. The results suggest that pretreatment with a selective copper-chelating compound can minimize retinal inflammation secondary to laser photocoagulation treatment, which may improve overall outcome of photocoagulation treatment for diabetic retinopathy.

Characterization and antitumor activity of triethylene tetramine, a novel telomerase inhibitor.

Triethylene tetramine (TETA) is a novel ligand for G-quadruplex and has been reported to have many kinds of biological activities, including telomerase inhibition, inducing the senescence of tumor cells, etc. In this study, tumor inhibiting activity of TETA and its mechanism were investigated in HeLa cells, MCF-7 cells and mice transplanted with S180 tumor. Results indicated that TETA inhibited telomerase activity involved in decreasing the expression of human telomerase reverse transcriptase (hTERT). We also observed that a low concentration of TETA had limited ability to inhibit the growth of tumor cells in short-term culture, but it could significantly enhance antitumor activity of traditional antitumor drugs in vitro and in vivo.