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This study investigates the effect of three new platinum complexes: Pt2(2,4-dimethylpyridine) 4(berenil)2 (Pt14), Pt2(3,4-dimethylpyridine)4(berenil)2 (Pt15) and Pt2(3,5-dimethylpyridine) 4(berenil)2 (Pt16) on growth and viability of breast cancer cells and their putative mechanism(s) of cytotoxicity. Cytotoxicity was measured with MTT assay and inhibition of [3H]thymidine incorporation into DNA in both breast cancer cells. Results revealed that Pt14-Pt16 exhibit substantially greater cytotoxicity than cisplatin against MCF-7 and MDAMB- 231 breast cancer cells. In the case of human skin fibroblast cell, cytotoxicity assays demonstrated that these compounds are less toxic to normal cells than cisplatin. In addition, the effects of Pt14-Pt16 are investigated using the flow cytometry assessment of annexin V binding, analysis of mitochondrial potential, markers of apoptosis such as caspase-3, caspase-8, caspase-9, caspase-10 and defragmentation of DNA by TUNEL assay. These results indicate that Pt14-Pt16 induce apoptosis by the mitochondrial and external pathway. [ABSTRACT FROM AUTHOR]

A series of six 2,5-disubstituted 1,3,4-thiadiazole derivatives was synthesized and examined for cytotoxic activity in MCF-7 and MDA-MB-231 breast cancer cells. MTT assay confirmed that 2-(3-fluorophenylamino)-5-(3-hydroxyphenyl)-1,3,4-thiadiazole (2), 2-(4-bromophenylamino)-5-(2,4-dichlorophenyl)-1,3,4-thiadiazole (3), 2-(4-fluorophenylamino)-5-(2,4-dichlorophenyl)-1,3,4-thiadiazole (4), had ability to inhibit MCF-7 and MDA-MB-231 cells proliferation. The IC50values for the mentioned compounds ranged between 120 and 160 μM (with respect to MCF-7 cells) and from 70 to 170 μM (with respect to MDA-MB-231 cells). It turned out, moreover, that compound2is a human topoisomerase II (topoII) catalytic inhibitor whereas the two other compounds (i.e.3and4) are capable of stabilizing DNA-topoII cleavage complex and thus are topoII poisons. [ABSTRACT FROM AUTHOR]

Abstract: A series of sildenafil analogues and aniline substituted pyrazolo[4,3-e][1,2,4]triazine sulfonamides were prepared and evaluated as carbonic anhydrase (CA, EC 4.2.1.1) inhibitors and for their anticancer activity against two human breast cancer cell lines (MCF-7, MDA-MB-231). The new compounds were ineffective as CA I inhibitors, poorly inhibited CA II, but were more effective against the tumor-associated isoforms CA IX and XII, with some compounds acting as low nanomolar inhibitors. Evaluation of the cytotoxicity by using an MTT assay, the inhibition of [3H]thymidine incorporation into DNA as well as collagen synthesis inhibition, demonstrated that these sulfonamides exhibit cytotoxic effects on breast cancer cell lines ex vivo. [Copyright &y& Elsevier]

A series of eight thiosemicarbazide derivatives was examined for cytotoxicity in breast cancer cell cultures. Among them, 4-benzoylthiosemicarbazides proved to be only slightly less potent than chlorambucil in both MDA-MB-231 and MCF-7 lines. In contrast, 4-aryl/alkylthiosemicarbazides revealed significantly lower cytotoxicity effect. Subsequently, all titled compounds were tested as potential human topoisomerase I and II (topo I and topo II) inhibitors. Mechanistic studies revealed that tested thiosemicarbazides act as both topoisomerase I and topoisomerase II inhibitors. Among them, the best inhibitory activity was found for 4-benzoylthiosemicarbazides ( 1 and 2) with IC50 at 50 µM against topo II. [ABSTRACT FROM AUTHOR]

In this study, we looked at the effect of ouabain, digoxin and proscillaridin A on human fibroblasts. These data show that low concentrations of ouabain, digoxin and proscillaridin A can activate proliferation of human fibroblasts, suggesting that the Na+, K+-adenosine triphosphatase complex may act as a transducing receptor. It was shown that 30 nM ouabain, digoxin and proscillaridin A stimulated an antiapoptotic action by the increase in the level of phosphorylated extracellular signal-regulated kinases (P-ERK 1/2). Ouabain, digoxin and proscillaridin A only at the relatively high concentration of 300 nM increased intracellular Ca2+ concentration, activated caspase-3 and induced apoptosis in human fibroblasts. In terms of reduction in cell viability, antiproliferative and apoptotic activity, these cardiac glycosides rank in the order proscillaridin A >digoxin >ouabain. [ABSTRACT FROM AUTHOR]

A number of novel cyclic amidine analogs of chlorambucil were synthesized and examined for cytotoxicity in breast cancer cell cultures and for inhibition of topoisomerases I and II. Evaluation of the cytotoxicity of these compounds employing a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide 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 active than chlorambucil. The degree to which these compounds inhibited cell growth breast cancer cells was directly correlated to DNA-binding affinity. These studies indicate that cyclic amidine analogs of chlorambucil are a potent catalytic inhibitor of topoisomerase II but not topoisomerase I. The highest degree of DNA binding and cytotoxicity in both MDA-MB-231 and MCF-7 breast cancer cells was observed for the compound, which possess a 4,5-dihydro-1H-imidazol moiety. [Copyright &y& Elsevier]

New sulfonamide derivatives of pyrazolo[4,3- e ][1,2,4]triazine were synthesized and investigated as antitumor agents through carbonic anhydrase (CA, EC 4.2.1.1) inhibition. The newly prepared compounds were tested for their anticancer activity against human breast cancer cell lines (MCF-7, MDA-MB-231) using a MTT assay and inhibition of [ 3 H]thymidine incorporation into DNA. Preliminary biological studies with several CA isoforms, revealed that the new derivatives were ineffective as CA I and II inhibitors, but they showed activity against tumor-associated enzymes, such as CA IX. The most effective inhibitor against CA IX was compound 8e that exhibited an inhibition constant K I of 13.8 nM, and derivatives 8c – 8d with moderate activity ( 8c : K I = 25.4 nM; 8d : K I = 24.5 nM). Compounds 8g – 8h exhibited acceptable activity ( 8g : K I = 27.7 nM; 8d : K I = 26.6 nM). The detailed synthesis, spectroscopic and biological data are also reported. [ABSTRACT FROM AUTHOR]

Nine carbocyclic analogues of mono- and bis-lexitropsins and two analogues of pentamidine with unsubstituted N-terminal amine group were synthesized. We have investigated the cytotoxic activity of new aromatic analogues of DNA binding ligands in MCF-7 breast cancer cells and assessed their ability to act as inhibitors of topoisomerase I and II. These studies indicate that aromatic analogues of bis-netropsin contain two identical units tethered by alkyloxyl chains are a potent catalytic inhibitor of both topoisomerases and exhibit moderate cytotoxicity in MCF-7 breast cancer cells. [Copyright &y& Elsevier]

Abstract: 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. [Copyright &y& Elsevier]