Development of near-infrared region luminescent N-acetyl-L-cysteine-coated Ag2S quantum dots with differential therapeutic effect

Aim: N-acetyl-L-cysteine (NAC) is a free radical scavenger. We developed NAC-coated Ag2S (NAC-Ag2S) quantum dot (QD) as an optical imaging and therapeutic agent. Materials & methods: QDs were synthesized in water. Their optical imaging potential and toxicity were studied in vitro. Results: NAC-Ag2S QDs have strong emission, that is tunable between 748 and 840 nm, and are stable in biologically relevant media. QDs showed significant differences both in cell internalization and toxicity in vitro. QDs were quite toxic to breast and cervical cancer cells but not to lung derived cells despite the higher uptake. NAC-Ag2S reduces reactive oxygen species (ROS) but causes cell death via DNA damage and apoptosis. Conclusion: NAC-Ag2S QDs are stable and strong signal-generating theranostic agents offering selective therapeutic effects

Pd(II) and Pt(II) saccharinate complexes of bis(diphenylphosphino) propane/butane: Synthesis, structure, antiproliferative activity and mechanism of action

[M(sac)(2)(dppp)] (1 and 2), [M(dppp)(2)](sac)(2) (3 and 4) and [M(sac)(2)(dppb)] (5 and 6) complexes, where M = Pd-II (1, 3 and 5) and Pt-II (2, 4 and 6), sac = saccharinate, dppp = 1,3-bis(diphenylphosphino)propane and dppb = 1,4-bis(diphenylphosphino)butane, were synthesized and characterized by IR, NMR, ESI-MS and X-ray diffraction. The anticancer activity of the complexes against human lung (A549), breast (MCF-7), prostate (DU145) and colon (HCT116) cancer cell lines showed that the cationic complexes of dppp (3 and 4) and neutral Pt complex of dppb (6) were the most active agents of series. 3 and 4 exhibited antiproliferative activity, while 6 was highly cytotoxic compared to cisplatin. These complexes were therefore subjected to further investigations to ascertain the possible role of lipophilicity, cellular uptake and DNA/EISA binding in their biological activity. Flow cytometry analysis revealed that complex 6 induced apoptotic cell death in A549 and HCT116 cells and caused the cell cycle arrest at the S phase and overproduction of reactive oxygen species (ROS), giving rise to mitochondria) depolarization and DNA damage. (C) 2018 Elsevier Masson SAS. All rights reserved

Novel 5-fluorouracil complexes of Zn(II) with pyridine-based ligands as potential anticancer agents

A series of novel Zn(II) complexes of 5-fluorouracilate (5-FU), namely (Zn(5-FU)(2)(bpy)] (1), [Zn(5-FU)(2)(phen)] (2), [Zn(5-FU)(2)(dpya)]center dot H2O (3), [Zn(5-FU)(2)(bpyma)]center dot 2H(2)O (4) and [Zn(5-FU)(2)(terpy)]center dot H2O(5), were synthesized and structurally characterized by spectroscopic methods and X-ray crystallography. 5-FU was coordinated to Zn(II) via the deprotonated N3 site and also presented the N1 and N3 linkage isomerism in 4 and 5 due to its tautomerism. The antiproliferative activity of the complexes was studied against lung (A549), breast (MDA-MB-231), colon (HCT116) and prostate (DU145) cancer cell lines. Complexes 1, 4 and 5 except 2 and 3 showed potent growth inhibitory activity towards selected cancer cells. Remarkably, 4 was highly cytotoxic towards A549 and MDA-MB-231 cell lines, being more active than the clinical drugs cisplatin and 5-FU. In addition, 4 was not toxic to normal lung cells (BEAS-2B). The complex exhibited a significantly high affinity towards DNA as assessed by gel electrophoresis and DNA docking. The mechanistic studies of 4 in A549 cells indicated that the complex induced apoptotic cell death as evidenced via caspase 3/7 activity, Bcl2 inactivation, annexin V and DAPI/PI staining. 4 further elevated the levels of reactive oxygen species (ROS), depolarized mitochondria and enhanced the expression of gamma-H2AX, thus contributing to its remarkable anticancer activity

Structural studies and cytotoxic activity of a new dinuclear coordination compound of palladium(II)-2,2:6,2-terpyridine with rigid dianionic 1,2,4-triazole-3-sulfonate linker

WOS: 000439744200011A new dinuclear coordination compound of palladium(II), [Pd-2(terpy)(2)(-tas-N-1,N-4)]SO(4)11H(2)O (1), was synthesized by tethering a doubly deprotonated 1,2,4-triazole-3-sulfonate (tas) linker generated in situ via oxidation of 1,2,4-triazole-3-thione (tat) under the synthetic conditions. X-ray diffraction analysis reveals that tat molecules adopt the thione form in the solid state, and are combined in infinite chains by symmetrically related classical intermolecular hydrogen bonds N1H1S1, N3H3N2 to give rise to R-2(2)(7) pattern in one-dimensional chains along the b-axis propagating along the a-axis. Further short contacts through lone pairs of N2S1 on the rings between the adjacent chains along the a-axis lead to a two-dimensional network structure. Compound 1 was characterized using infrared, H-1 NMR and UV-visible spectroscopies, electrospray ionization mass spectrometry and X-ray crystallography. The crystal structure determination of 1 reveals that the Pd(II) ions are coordinated with four nitrogen atoms: three from terpy and one from tas acting as an end-to-end (-1,4) bridging ligand. The Pd(II) ions in 1 adopt a distorted square planar geometry. The anti-growth effect of 1 was tested on colorectal cancer (HCT-15), non-small-cell lung cancer (A549), prostate cancer (PC-3) and cervical cancer (HeLa) cell lines using sulforhodamine B viability assay. The cytotoxic effect was further confirmed using adenosine triphosphate viability assay. Compound 1 shows a promising cytotoxic activity in the diverse cancer cell models in vitro (p <0.0001).Turkish Scientific and Technical Research Council (TUBITAK)Turkiye Bilimsel ve Teknolojik Arastirma Kurumu (TUBITAK) [214Z090]Turkish Scientific and Technical Research Council (TUBITAK), Grant/Award Number: 214Z09

Water-soluble copper(ii) 5-fluorouracil complexes bearing polypyridyl co-ligands: synthesis, structures and anticancer activity

Five newly synthesized copper(ii) 5-fluorouracil (5-FU) complexes of polypyridyl co-ligands with good solubility in water, namely [CuCl(5-FU)(bpy)(DMSO)] (1), [Cu(5-FU)(phen)2](5-FU)·4H2O (2), [Cu(5-FU)(dpya)2](NO3)·2.5H2O (3), [Cu(5-FU)(NO3)(bpyma)]·H2O (4) and [CuCl(5-FU)(terpy)] (5) (bpy = 2,2′-bipyridine, phen = 1,10-phenanthroline, dpya = 2,2′-dipyridylamine, bpyma = bis(2-pyridylmethyl)amine and terpy = 2,2′;6′,2′′-terpyridine), were characterized by elemental analysis and a number of spectrometric methods. The structures of complexes 1-5 were determined by X-ray crystallography and the copper(ii) ions were five coordinate. Cytotoxic activity of the complexes in four human cancer cell lines, A549 (lung carcinoma), MDA-MB-231 (breast carcinoma), HCT116 (colon carcinoma) and DU145 (prostate carcinoma), and a normal cell line, BEAS-2B (human lung epithelial), was determined by SRB assay and compared with that of 5-FU and cisplatin. The complexation of 5-FU together with polypyridyl ligands resulted in a significant increase in the cytotoxicity of the complexes, with complex 2 exhibiting the highest anticancer potency against all the cell lines, with HCT116 being the most sensitive. The mode of action of cell death for 2 was investigated using morphological imaging and cytometric analyses, including the capacity for induction of apoptosis, generation of reactive oxygen species, mitochondrial dysfunction and DNA damage

Mixed ligand complexes of Co(II), Ni(II) and Cu(II) with quercetin and diimine ligands: synthesis, characterization, anti-cancer and anti-oxidant activity

In this work, mixed ligand complexes of Co(II) Ni(II) and Cu(II) were synthesized using quercetin and diimine (1,10-phenanthroline or 2,2 '-bipyiridine) ligands. The obtained Ni(II) and Co(II) complexes are new and the Cu(II) complexes are synthesized by different method from the literature. The characterization of complexes was performed by elemental analysis, thermogravimetric analysis, ESI-MS, UV-visible and infrared spectral analyses, magnetic susceptibility and molar conductivity measurements. It was found that quercetin, diimine and metal(II) ion form 1:1:1 complexes. Resulting data supported octahedral geometry for Ni(II) and Co(II) complexes and square pyramidal geometry for Cu(II) complexes. The proposed compositions are [Co(queH-1)Cl(phen)(H2O)]center dot 2H(2)O (1, queH = quercetin, phen = 1,10-phenanthroline), [Ni(queH-1)Cl(phen)(H2O)]center dot 2H(2)O (2), [Cu(queH-1)Cl(phen)]center dot 2.5H(2)O (3) and [Cu(queH-1)Cl(bpy)]center dot 2H(2)O (4, bpy = 2,2 '-bipyiridine). Antioxidant capacity and total phenolic content of complexes measured by Folin-Ciocalteu and ABTS methods. Anti-cancer effect of these compounds were tested against different cancer cells (A549, PC-3, HeLa and MCF-7). Apoptosis identified by the fluorescence imaging, caspase cleaved cytokeratin-18 and flow cytometry analysis (annexin V, caspase 3/7, mitochondria membrane potential and oxidative stress). As a result, Cu(II) complexes are more effective than the other compounds and Complex 3 is a promising anti-cancer compound against breast cancer MCF-7 and MDA-MB-231 cells (IC50 values are 2.4 and 5.4 mu M for 48 h, respectively). Flow cytometry analysis exhibited that Complex 3 caused apoptosis in MCF-7 cells. These results support that Complex 3 has anticancer activity and can be a potential anticancer agent especially in breast cancer

Synthesis, characterization, anticancer and antioxidant activity of new nickel(II) and copper(II) flavonoid complexes

Flavonoids are natural products which are known to have biological activity for human health. In this study, new mixed ligand complexes of Ni(II) and Cu(II) were synthesized by using flavonoid (quercetin or naringenin) and heterocyclic imine (2,2':6',2 ''-terpyridine or 2,2'-bipyiridine) ligands. The new complexes are [Ni(narH-1)(terpy)Cl]center dot 4H(2)O (1, nar = naringenin, terpy = 2,2':6',2 ''-terpyridine), [Cu(narH-1)(terpy)Cl]center dot H2O (2), and [Cu(queH-1)(bpy)(O3N)]center dot 1.5H(2)O (3, que = quercetin, bpy = 2,2'-bipyiridine). The structural features of the synthesized mixed ligand complexes were investigated using elemental analysis, thermogravimetric analysis, Fourier transform infrared spectroscopy, magnetic susceptibility and molar conductivity measurements. The resulting data demonstrated an octahedral geometry for Complex 1 and Complex 2 and square pyramidal geometry for Complex 3. Antioxidant capacity and total phenolic content of Complexes 1-3 were measured by the Folin-Ciocalteu and ABTS methods. Anti- proliferative effect of complexes were tested by SRB and ATP assays on MCF-7 (breast cancer), A549 (nonsmall cell lung cancer), PC-3 (prostate cancer) and HeLa (human cervical cancer) cell lines. Apoptosis was identified using by the fluorescence imaging, caspase cleaved cytokeratin-18 and flow cytometry analysis. Complex 2 and 3 had high total phenolic content and antioxidant activity. Complex 2 was found to show selective cytotoxicity through the induction of apoptosis on MCF-7 cells with having a very low IC50 value ( 50 mu M). In conclusion, Complex 2 is a highly promising and novel compound for breast cancer and warrants further animal experiments. (C) 2019 Elsevier B.V. All rights reserved

Targeting Periostin Expression Makes Pancreatic Cancer Spheroids More Vulnerable to Natural Killer Cells

Pancreatic cancer (PaCa) characteristically has a dense tumor microenvironment, which results in poor patient prognosis. Pancreatic stellate cells (PSCs) are the most abundant cells in the PaCa microenvironment and the principal source of collagen. Periostin, a matricellular protein, is produced specifically by PSCs and promotes the aggressiveness of PaCa cells by facilitating extracellular collagen assembly. Here, we aimed to decrease extracellular collagen assembly by suppressing periostin, thereby increasing the cytotoxic activity of natural killer (NK) cells. Periostin expression was suppressed in PSCs (called PSC-P) using CRISPR-Cas9. PaCa cells (BxPC-3) were co-cultured with PSC and PSC-P cells in a 3D environment to form tumor spheroids mimicking the tumor microenvironment. The extracellular collagen production of spheroids was evaluated by Masson&rsquo;s trichrome staining. The cytotoxic activity of NK-92 cells was analyzed by flow cytometry and confocal microscopy via CD107a staining. Cell death in BxPC-3 cells was evaluated by measuring Annexin-V and PI positivity using flow cytometry. As a result, periostin suppression decreased extracellular collagen and increased the infiltration of NK-92 cells into spheroids, and induced cell death in PaCa cells. In conclusion, we suggest that periostin might be a therapeutic target for PaCa and further analysis is warranted using in vivo models for proof-of-concept

Targeting Periostin Expression Makes Pancreatic Cancer Spheroids More Vulnerable to Natural Killer Cells

Pancreatic cancer (PaCa) characteristically has a dense tumor microenvironment, which results in poor patient prognosis. Pancreatic stellate cells (PSCs) are the most abundant cells in the PaCa microenvironment and the principal source of collagen. Periostin, a matricellular protein, is produced specifically by PSCs and promotes the aggressiveness of PaCa cells by facilitating extracellular collagen assembly. Here, we aimed to decrease extracellular collagen assembly by suppressing periostin, thereby increasing the cytotoxic activity of natural killer (NK) cells. Periostin expression was suppressed in PSCs (called PSC-P) using CRISPR-Cas9. PaCa cells (BxPC-3) were co-cultured with PSC and PSC-P cells in a 3D environment to form tumor spheroids mimicking the tumor microenvironment. The extracellular collagen production of spheroids was evaluated by Masson’s trichrome staining. The cytotoxic activity of NK-92 cells was analyzed by flow cytometry and confocal microscopy via CD107a staining. Cell death in BxPC-3 cells was evaluated by measuring Annexin-V and PI positivity using flow cytometry. As a result, periostin suppression decreased extracellular collagen and increased the infiltration of NK-92 cells into spheroids, and induced cell death in PaCa cells. In conclusion, we suggest that periostin might be a therapeutic target for PaCa and further analysis is warranted using in vivo models for proof-of-concept