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High Cytotoxicity (high + cytotoxicity)
Selected AbstractsCharacterization by NMR Spectroscopy, X-ray Analysis and Cytotoxic Activity of the Ruthenium(II) Compounds [RuL3](PF6)2(L = 2-Phenylazopyridine or o -Tolylazopyridine) and [RuL'2L"](PF6)2(L', L" = 2-Phenylazopyridine, 2,2'-Bipyridine)EUROPEAN JOURNAL OF INORGANIC CHEMISTRY, Issue 13 2005Anna C. G. Hotze Abstract Tris(ligand) complexes [RuL3](PF6)2 (L = 2-phenylazopyridine or o -tolylazopyridine) and mixed ligand [RuL'2L"](PF6)2 (L' and L" are 2-phenylazopyridine or 2,2'-bipyridine) have been synthesized, structurally characterized and investigated for cytotoxic activity. These complexes are important to study the hypothesis that the compound ,-[Ru(azpy)2Cl2] (azpy = 2-phenylazopyridine) exhibits a high cytotoxicity due to its two cis chloride ligands, which might be exchanged for biological targets as DNA. Molecular structures of mer -[Ru(azpy)3](PF6)2 (1) and mer -[Ru(tazpy)3](PF6)2 (5) (tazpy = o -tolylazopyridine) have been determined by X-ray diffraction. Series of complexes [RuL3](PF6)2 and [RuL'2L"](PF6)2 show interesting NMR spectroscopic data; e.g. the spectrum of mer -[Ru(azpy)3](PF6)2 (1) shows extremely broadened resonances at room temp. but sharpened resonances at low temperature. In the 1H NMR spectra of compounds [Ru(azpy)2(bpy)]2+ and [Ru(bpy)2(azpy)]2+ (bpy = 2,2-bipyridine), respectively, less broadened (room temp.) or completely sharp resonances (room temp.) occur in comparison to 1 (under same conditions). By selecting the right temperature and/or concentration, NMR spectra of these series of compounds have been resolved using 2D COSY and NOESY NMR spectroscopy. Remarkably, the cytotoxicity data against a series of human tumor cell lines (A498, EVSA-T, H226, IGROV, M19, MCF-7 and WIDR) show a moderate cytotoxicity for these series of tris(ligand) complexes. So, even though no chloride ligands are present in these tris(ligand) complexes, a considerable cytotoxic activity is observed. This would imply that the 2-phenylazopyridine ruthenium(II) complexes act by a completely different mechanism than the well-known cisplatin. This finding is important, because an anticancer compound acting via a different mechanism is a prerequisite in designing new anticancer drugs. (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2005) [source] Effects of histone deacetylase inhibitors on p55CDC/Cdc20 expression in HT29 cell lineJOURNAL OF CELLULAR BIOCHEMISTRY, Issue 4 2006Giuseppe Iacomino Abstract In a previous work, taking advantage of the gene-array screening technology, we analysed the effects of histone deacetylase (HDAC) inhibitor sodium butyrate (NaBt), on gene transcription in HT29 human adenocarcinoma cell line. In this study, we focused our attention on p55CDC/Cdc20 gene, whose expression was dramatically reduced by NaBt treatment. Mammalian p55CDC/Cdc20 interacts with the anaphase promoting complex/cyclosome (APC/C), and is involved in regulating anaphase onset and late mitotic events. Using NaBt and trichostatin A (TSA), a member of the HDAC inhibitor family, we showed that both HDAC inhibitors totally downregulated p55CDC/Cdc20 transcription and expression. Cell cycle analysis demonstrated that NaBt arrested HT29 cells in G0/G1 phase, while TSA caused a double block in G0/G1 and G2/M phases. Moreover, p55CDC/Cdc20 showed maximal expression in S and G2/M phases of HT29 cell division cycle. Based on this evidence, and by means of specific cell cycle modulators, such as nocodazole and hydroxyurea, we demonstrated that both TSA and NaBt were responsible for loss of p55CDC/Cdc20 expression, but with different mechanisms of action. Taken together, these results suggest that targeting molecules involved in spindle mitotic checkpoint, such as p55CDC/Cdc20, might account for the high cytotoxicity of HDAC inhibitors versus malignant cells. J. Cell. Biochem. 99: 1122,1131, 2006. © 2006 Wiley-Liss, Inc. [source] Suppression of growth of pancreatic cancer cell and expression of vascular endothelial growth factor by gene silencing with RNA interferenceJOURNAL OF DIGESTIVE DISEASES, Issue 4 2008Jian WANG OBJECTIVE: To explore the anti-angiogenesis and tumor cell growth suppressive effects resulted from gene silencing by RNAi in BxPC-3 human pancreatic cancer cells. METHODS: The designation and transfection of vascular endothelial growth factor (VEGF)-siRNA lentivirus was carried out in vitro. Real-time PCR and western blot were conducted to measure the expression levels of VEGF mRNA and protein. Flow cytometry was employed to evaluate cell apoptosis and cell death. A lactate dehydrogenase (LDH) assay was used to assess the cytotoxicity of VEGF-siRNA. A 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT) assay was used to picture the cellular growth. For the in vivo study, BxPC-3 cells were injected subcutaneously into nude mice to form xenografts. The mice were divided into three groups according to the intervention used. The control group, the negative control group and the knockdown group of mice were injected with saline, an empty lentivirus vehicle and lentivirus carrying VEGF-siRNA, respectively. None of the mice died during the study. When these mice were killed, the xenografts were collected and the tumor sizes of the different groups were compared. Finally, immunohistochemistry was used to assess the VEGF expression level and microvascular density. RESULTS: After the transfection of VEGF-siRNA lentivirus, the cellular expression of VEGF mRNA decreased to 50% of the control and the VEGF protein in the BxPC-3 cells decreased to 30% of the control. Apoptosis and cell death increased after transfection of the VEGF-siRNA lentivirus. The LDH assay showed high cytotoxicity induced by VEGF-siRNA lentivirus transfection. The MTT assay showed slower cellular growth in the knockdown cells. Tumor growth suppression was observed in nude mice that had received the VEGF-siRNA lentivirus transfection, and the tumor sizes of the xenografts in this group were clearly smaller than those in other two groups. VEGF expression and microvascular density were significantly decreased. CONCLUSION: Vascular endothelial growth factor gene silencing via VEGF-siRNA can effectively inhibit the production of VEGF and exert an anti-angiogenesis and tumor cell growth suppressive effect both in vitro and in vivo. [source] Gastroprotective and cytotoxic effect of semisynthetic ferruginol derivativesJOURNAL OF PHARMACY AND PHARMACOLOGY: AN INTERNATI ONAL JOURNAL OF PHARMACEUTICAL SCIENCE, Issue 2 2007Carlos Areche The gastroprotective abietane diterpene ferruginol has been shown to present high cytotoxicity. In order to obtain active compounds with less cytotoxicity, 18 semisynthetic ferruginol derivatives and totarol were assessed for their gastroprotective effects in the HCl/ethanol-induced gastric lesion model in mice, as well as for cytotoxicity in human gastric epithelial cells (AGS) and human lung fibroblasts (MRC-5). At 20 mg kg,1, the greatest gastroprotective effects were provided by abieta-8,11,13-triene (1), abieta-8,11,13-trien-12-yl-2-chloropropanoate (8), abieta-8,11,13-trien-12-yl propenoate (9), 12-(2,3,4,6-tetra- O -acetyl-,-D-glucopyranosyloxy)-abieta-8,11,13-triene (17) and 12-(,-D-galactopyranosyloxy)-abieta-8,11,13-triene (18), all of which were as active as the reference drug lansoprazole at 20 mg kg,1, reducing gastric lesions by 69, 76, 67, 72 and 61%, respectively. No relation was observed between lipophilicity and the gastroprotective effect. Compounds that showed the greatest cytotoxicity towards AGS cells were ferruginol (2), the corresponding formate (5), acetate (6), propionate (7), 8, 9, 12-(,-D-glucopyranosyloxy)-abieta-8,11,13-triene (16), 18 and totarol (20) (IC50 18,44 ,M). Ferruginol and compounds 5,9, 16, 18 and 20 were the most toxic compounds against fibroblasts (IC50 19,56 ,M), with a correlation to AGS cells. The derivative 19 was much more active against AGS cells than towards fibroblasts. The best activity/cytotoxicity ratio was found for compound 17, with a lesion index comparable with lansoprazole at 20 mg kg,1 and cytotoxicity >1000 ,M towards MRC-5 and AGS cells, respectively. In conclusion, some derivatives showed a better gastroprotective effect/cytotoxicity ratio than the parent compound ferruginol. A total of 13 new compounds are reported here for the first time. [source] Comparative study of eight well-known polyphenolic antioxidantsJOURNAL OF PHARMACY AND PHARMACOLOGY: AN INTERNATI ONAL JOURNAL OF PHARMACEUTICAL SCIENCE, Issue 9 2003P. Cos ABSTRACT Eight antioxidants from five different polyphenolic classes (cinnamic acids, benzoic acids, flavonoids, proanthocyanidins and stilbenes), and the water-soluble vitamin E derivative trolox were examined for their antioxidant activity in-vitro. In addition, the compounds were tested for their cytotoxicity on growing fibroblasts and their inhibition of the classical pathway of the complement system. Procyanidin C1 was shown to be a good scavenger of both DPPH* and HO*, and a strong inhibitor of lipid peroxidation and the classical pathway of the complement system. Consequently, procyanidin C1 was classified as the most promising antioxidant in-vitro of all compounds tested. In contrast, genistein exhibited a very low antioxidant activity in both the lipid peroxidation and the DPPH* scavenging assay, a high cytotoxicity and a low complement-inhibiting activity. [source] Brush-Like Amphoteric Poly[isobutylene- alt -(maleic acid)- graft -oligoethyleneamine)]/DNA Complexes for Efficient Gene TransfectionMACROMOLECULAR RAPID COMMUNICATIONS, Issue 13 2010Majad Khan Abstract Synthetic gene delivery vectors, especially cationic polymers have attracted enormous attention in recent decades because of their ease of manufacture, targettability, and scaling up. However, certain issues such as high cytotoxicity and low transfection efficiency problems have hampered the advance of nonviral gene delivery. In this study, we designed and synthesized brush-like amphoteric poly[isobutylene- alt -(maleic acid)- graft -oligoethyleneamine] capable of mediating highly efficient gene transfection. The polymers are composed of multiple pendant oligoethyleneimine molecules with alternating carboxylic acid moiety grafted onto poly[isobutylene- alt -(maleic anhydride)]. The polymer formed from pentaethylenehexamine {i.e., poly[isobutylene- alt -(maleic acid)- graft -pentaethylenehexamine)]} was able to condense DNA efficiently into nanoparticles of size around 200,nm with positive zeta potential of about 28,30,mV despite its amphoteric nature. Luciferase expression level and percentage of GFP expressing cells induced by this polymer was higher than those mediated with polyethyleneimine (branched, 25,kDa) by at least one order of magnitude at their optimal N/P ratios on HEK293, HepG2, and 4T1 cells. In vitro cytotoxicity testing revealed that the polymer/DNA complexes were less cytotoxic than those of PEI, and the viability of the cells after being incubated with the polymer/DNA complexes at the optimal N/P ratios was higher than 85%. This polymer can be a promising gene delivery carrier for gene therapy. [source] Cytotoxicity in vitro of naphthazarin derivatives from Onosma arenariaPHYTOTHERAPY RESEARCH, Issue 7 2006Tatjana Kundakovi Abstract The cytotoxicity of naphthazarin derivatives isolated from the roots of Onosma arenaria on human cervix adenocarcinoma cells (HeLa) and leukaemia K562 cells, as well on non-malignant peripheral blood mononuclear cells (PBMC) was studied. The results show that , -hydroxyisovalerylalkannin, acetylalkannin and the pigment fraction exhibited high cytotoxicity in vitro against the tested cell lines, as well the healthy PBMC before or after activation with phytohaemagglutinin. Copyright © 2006 John Wiley & Sons, Ltd. [source] Structural features for the mechanism of antitumor action of a dimeric human pancreatic ribonuclease variantPROTEIN SCIENCE, Issue 1 2009Antonello Merlino Abstract A specialized class of RNases shows a high cytotoxicity toward tumor cell lines, which is critically dependent on their ability to reach the cytosol and to evade the action of the ribonuclease inhibitor (RI). The cytotoxicity and antitumor activity of bovine seminal ribonuclease (BSRNase), which exists in the native state as an equilibrium mixture of a swapped and an unswapped dimer, are peculiar properties of the swapped form. A dimeric variant (HHP2-RNase) of human pancreatic RNase, in which the enzyme has been engineered to reproduce the sequence of BSRNase helix-II (Gln28,Leu, Arg31,Cys, Arg32,Cys, and Asn34,Lys) and to eliminate a negative charge on the surface (Glu111,Gly), is also extremely cytotoxic. Surprisingly, this activity is associated also to the unswapped form of the protein. The crystal structure reveals that on this molecule the hinge regions, which are highly disordered in the unswapped form of BSRNase, adopt a very well-defined conformation in both subunits. The results suggest that the two hinge peptides and the two Leu28 side chains may provide an anchorage to a transient noncovalent dimer, which maintains Cys31 and Cys32 of the two subunits in proximity, thus stabilizing a quaternary structure, similar to that found for the noncovalent swapped dimer of BSRNase, that allows the molecule to escape RI and/or to enhance the formation of the interchain disulfides. [source] Mechanism of tyrosinase inhibition by deoxyArbutin and its second-generation derivativesBRITISH JOURNAL OF DERMATOLOGY, Issue 6 2008S. Chawla Summary Background, Disorders, such as age spots, melasma and hyperpigmentation at sites of actinic damage, emanate from the augmentation of an increased amount of epidermal melanin. Objectives, The ineptness of current therapies in treating these conditions, as well as high cytotoxicity, mutagenicity, poor skin penetration and low stability of skin-depigmenting formulations led us to investigate new compounds that meet the medical requirements for depigmentation agents. We have shown previously that the tyrosinase inhibitor deoxyArbutin (dA) is a more effective and less toxic skin lightener than hydroquinone (HQ). Methods, The efficacy and reversibility of dA and its derivatives on inhibiting tyrosine hydroxylase and DOPAoxidase was assessed using standard assays. Results, dA and its second-generation derivatives inhibit tyrosine hydroxylase and DOPAoxidase activities of tyrosinase dose dependently thereby inhibiting melanin synthesis in intact melanocytes, when used at concentrations that retain 95% cell viability in culture. This depigmenting effect was completely reversible when the compounds were removed. Tyrosinase inhibition was also observed in vitro when tested using human and purified mushroom tyrosinase, establishing that they are direct enzyme inhibitors. Lineweaver,Burk reciprocal plot analysis using mushroom tyrosinase illustrated that dA and its derivatives are more robust competitive inhibitors than HQ, when tyrosine is used as substrate. Conclusions, Thus, dA and its second-generation derivatives, which inhibit melanogenesis at safe concentrations by specifically acting on the tyrosinase enzyme at a post-translational level, are promising agents to ameliorate hyperpigmented lesions or lighten skin. [source] Antitumor activity of chimeric immunoreceptor gene-modified Tc1 and Th1 cells against autologous carcinoembryonic antigen-expressing colon cancer cellsCANCER SCIENCE, Issue 9 2006Takeshi Sasaki To generate tumor-specific and interferon (IFN)-,-producing Tc1 and Th1 cells applicable for many cancer patients, we previously developed a protocol for generating carcinoembryonic antigen (CEA)-specific Tc1 and Th1 cells from healthy human T cells by transduction with a lentivirus containing a chimeric immunoglobulin T-cell receptor (cIgTCR) gene composed of single-chain variable fragments from an anti-CEA-specific monoclonal antibody fused to an intracellular signaling domain of CD28 and CD3,. These cells, designated Tc1-T and Th1-T bodies, respectively, showed strong antitumor activity against CEA-expressing tumor cells in RAG2,/, mice when both of them were transferred. However, it remains unclear whether it is possible to generate Tc1-T and Th1-T bodies from cancer patients with defective T-cell function because of significant immunosuppression. Here, we prepared Tc1-T and Th1-T bodies from T cells of a colon cancer patient, and asked whether these T bodies can exert effective T-cell function against autologous tumor cells. These T bodies showed high cytotoxicity and produced IFN-, in response to CEA-expressing autologous tumor cells, even in the presence of soluble CEA. It was also demonstrated that Th1-T bodies supported the survival of Tc1-T bodies through cell-to-cell interactions. Furthermore, our protocol utilized retrovirus for cIgTCR transduction to achieve better induction efficiency compared to lentivirus-mediated transduction. Taken together, our findings here indicate that retrovirally transduced Tc1-T and Th1-T bodies will become a promising strategy for adoptive immunotherapy of human cancer. (Cancer Sci 2006; 97: 920,927) [source] Synthesis and Antitumor Activity of Novel Dibutyltin Carboxylates of Aminoglucosyl DerivativesCHEMICAL BIOLOGY & DRUG DESIGN, Issue 6 2009Wei Li In this study, di-n-butyltin(IV) oxide was reacted with the amino glucose analog, cis -4-[N -(1,,3,,4,,6,-tetra- O -benzoyl-2-deoxy-glucopyranosyl)imido]-4-oxo-2-butenoic acid (1a) and o -[N -(1,,3,,4,,6,-tetra- O -benzoyl-2-deoxy-glucopyranosyl) carbamoyl] benzoic acid (2a) to give the complexes bis-{cis -4-[N -(1,,3,,4,,6,-tetra- O -benzoyl-2-deoxy-glucopyranosyl)imido-4-oxo-2-butenoic acid]-di-n-butyltin} carboxylate (1) and bis-{o -[N -(1,,3,,4,,6,-tetra- O -benzoyl-2-deoxy-glucopyranosyl) carbamoyl-benzoic acid]-di-n-butyltin}carboxylate (2). These two compounds were then characterized by IR, NMR and MS. In vitro tests showed that both compounds have high cytotoxicity in four tumor cell lines (P388, HL-60, A549 and BEL-7402). Clonogenic assays demonstrated that both compounds 1 and 2 have hematopoietic cell toxicity at 10,6 m. [source] Synthesis, Crystal Structure and in vitro Antitumor Activity of Di- n -butyltin p -[N, N -Bis(2-chloroethyl)amino]benzoatesCHINESE JOURNAL OF CHEMISTRY, Issue 12 2005Zhong-Wei Zhang Abstract Di- n -butyltin oxide reacted with p- [N,N -bis(2-chloroethyl)amino]benzoic acid to yield the compounds {{4-[(ClCH2CH2)2N]C6H4COOSnBu2}2O}2 (1) and {4-[(ClCH2CH2)2N]C6H4COO}2SnBu2 (2), which have been characterized by IR and 1H NMR spectra. The X-ray diffractional studies of 1 reveal the structure of the molecule to be a dimer, in which the two Bu2Sn groups were linked via two bridging oxygen atoms to form a central Bu4Sn2O2 unit. And the tin atom adopts two carbons from two n -butyl groups and three oxygen atoms from the acid and the bridging oxygen. In vitro test showed compound 1 to exhibit high cytotoxicity against P388 and HL-60 cell lines. [source] | ||||||||||||||||