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MicroRNAs (miRNAs) regulate a wide variety of biological processes, including tumourigenesis. Altered miRNA expression is associated with deregulation of signalling pathways, which in turn cause abnormal cell growth and de-differentiation, contributing to cancer. miR-143 and miR-145 are anti-tumourigenic and influence the sensitivity of tumour cells to chemotherapy and targeted therapy. Comparative proteomic analysis was performed in HCT116 human colon cancer cells stably transduced with miR-143 or miR-145. Immunoblotting analysis validated the proteomic data in stable and transient miRNA overexpression conditions in human colon cancer cells. We show that approximately 100 proteins are differentially expressed in HCT116 human colon cancer cells stably transduced with miR-143 or miR-145 compared to Empty control cells. Further, Gene Ontology and pathway enrichment analysis indicated that proteins involved in specific cell signalling pathways such as cell death, response to oxidative stress, and protein folding might be modulated by these miRNAs. In particular, antioxidant enzyme superoxide dismutase 1 (SOD1) was downregulated by stable expression of either miR-143 or miR-145. Further, SOD1 gain-of-function experiments rescued cells from miR-143-induced oxidative stress. Moreover, miR-143 overexpression increased oxaliplatin-induced apoptosis associated with reactive oxygen species generation, which was abrogated by genetic and pharmacological inhibition of oxidative stress. Overall, miR-143 might circumvent resistance of colon cancer cells to oxaliplatin via increased oxidative stress in HCT116 human colon cancer cells.

Estradiol-BODIPY linked via an 8-carbon spacer chain and 19-nortestosterone- and testosterone-BODIPY linked via an ethynyl spacer group were evaluated for cell uptake in the breast cancer cell lines MCF-7 and MDA-MB-231 and prostate cancer cell lines PC-3 and LNCaP, as well as in normal dermal fibroblasts, using fluorescence microscopy. The highest level of internalization was observed with 11β-OMe-estradiol-BODIPY 2 and 7α-Me-19-nortestosterone-BODIPY 4 towards cells expressing their specific receptors. Blocking experiments showed changes in non-specific cell uptake in the cancer and normal cells, which likely reflect differences in the lipophilicity of the conjugates. The internalization of the conjugates was shown to be an energy-dependent process that is likely mediated by clathrin- and caveolae-endocytosis. Studies using 2D co-cultures of cancer cells and normal fibroblasts showed that the conjugates are more selective towards cancer cells. Cell viability assays showed that the conjugates are non-toxic for cancer and/or normal cells. Visible light irradiation of cells incubated with estradiol-BODIPYs 1 and 2 and 7α-Me-19-nortestosterone-BODIPY 4 induced cell death, suggesting their potential for use as PDT agents. [ABSTRACT FROM AUTHOR]

The antiproliferative activity of [Mn(CO)3(N^N)Br] (N^N = phendione 1, bipy 3) and of the two newly synthesized Mn complexes [Mn(CO)3(acridine)(phendione)]OTf (2) and [Mn(CO)3(di-triazole)Br] (4) has been evaluated by MTS against three tumor cell lines A2780 (ovarian carcinoma), HCT116 (colorectal carcinoma), HCT116doxR (colorectal carcinoma resistant to doxorubicin), and in human dermal fibroblasts. The antiproliferative assay showed a dose-dependent effect higher in complex 1 and 2 with a selectivity toward ovarian carcinoma cell line 21 times higher than in human fibroblasts. Exposure of A2780 cells to IC50 concentrations of complex 1 and 2 led to an increase of reactive oxygen species that led to the activation of cell death mechanisms, namely via intrinsic apoptosis for 2 and autophagy and extrinsic apoptosis for 1. Both complexes do not target DNA or interfere with cell cycle progression but are able to potentiate cell migration and neovascularization (for 2) an indicative that their application might be directed for initial tumor stages to avoid tumor invasion and metastization and opening a new avenue for complex 2 application in regenerative medicine. Interestingly, both complexes do not show toxicity in both in vivo models (CAM and zebrafish). [ABSTRACT FROM AUTHOR]

The clinical success of cisplatin, carboplatin, and oxaliplatin has sparked the interest of medicinal inorganic chemistry to synthesize and study compounds with non-platinum metal centers. Despite Ru(II)–polypyridyl complexes being widely studied and well established for their antitumor properties, there are not enough in vivo studies to establish the potentiality of this type of compound. Therefore, we report to the best of our knowledge the first in vivo study of Ru(II)–polypyridyl complexes against breast cancer with promising results. In order to conduct our study, we used MCF7 zebrafish xenografts and ruthenium complexes [Ru(bipy)2(C12H8N6-N,N)][CF3SO3]2Ru1 and [{Ru(bipy)2}2(μ-C12H8N6-N,N)][CF3SO3]4Ru2, which were recently developed by our group. Ru1 and Ru2 reduced the tumor size by an average of 30% without causing significant signs of lethality when administered at low doses of 1.25 mg·L−1. Moreover, the in vitro selectivity results were confirmed in vivo against MCF7 breast cancer cells. Surprisingly, this work suggests that both the mono- and the dinuclear Ru(II)–polypyridyl compounds have in vivo potential against breast cancer, since there were no significant differences between both treatments, highlighting Ru1 and Ru2 as promising chemotherapy agents in breast cancer therapy. [ABSTRACT FROM AUTHOR]

• Synthesis of structural diverse arylidene anthrones. • Antiproliferative effect related to the imidazolium pattern of the heterocyclic. • The mechanism of cytotoxicity is different from that of doxorubicin. • Compounds showing antiproliferative selectivity towards ovarian cancer cells. New hetero-arylidene-9(10 H)-anthrone derivatives (1) were synthesized from reaction of 1,2-dimethyl-3-alkyl imidazolium salts (2) and 9-anthracenecarboxaldehyde. Ion exchange of the anion with dioctyl sulfosuccinate and lithium bis(trifluoromethanesulfonyl)imide led to the preparation of other derivatives. The antiproliferative effect of the compounds was evaluated in human ovarian (A2780) and colorectal (HCT116) carcinoma cell lines and in normal primary human fibroblasts. Compound 1 presented an antiproliferative effect related to the imidazolium pattern of substitution with compounds having a decyl group at the R-position (1c and 3c) showing the highest cytotoxic activities in all cell lines independently of the counter ion. Compounds 1b and 1c internalize A2780 cancer cells via a passive or an active transport, respectively, inducing A2780 cell death via an extrinsic apoptosis (1b) or intrinsic apoptosis and oncosis (1c). The localization of both compounds in the cytoplasm coupled to the absence of reactive oxygen species (ROS) induction suggest that the mechanisms of toxicity might be different than those of other anthracyclines currently used in chemotherapy. [ABSTRACT FROM AUTHOR]

The water-soluble 1D helical coordination polymer [Ag(Tpms)] n (1) [Tpms = tris(pyrazolyl)methane sulfonate, −O 3 SC(pz) 3 ; pz = pyrazolyl] was synthesized and fully characterized, its single-crystal X-ray diffraction analysis revealing the ligand acting as a bridging chelate N 3 -donor ligand. The antiproliferative potential of 1 was performed on two human tumour cell lines, A2780 and HCT116, and in normal fibroblasts, with a much higher effect in the former cell line (IC 50 of 0.04 μM) as compared to the latter cell line and to normal fibroblasts. Compound 1 does not alter cell cycle progression but interferes with the adherence of A2780 cells triggering cell apoptosis. Apoptosis appears to occur via the extrinsic pathway (no changes in mitochondria membrane potential, reactive oxygen species (ROS) and pro-apoptotic (B-cell lymphoma 2 (BCL-2) associated protein (BAX))/anti-apoptotic (BCL-2) ratio) being this hypothesis also supported by the presence of silver mainly in the supernatants of A2780 cells. Results also indicated that cell death via autophagy was triggered. Proteomic analysis allowed us to confirm that compound 1 is able to induce a stress response in A2780 cells that is related with its antiproliferative activity and the trigger of apoptosis. The polymer [Ag(tris(pyrazolyl)methane sulfonate)]n was synthesized and characterized. A cytotoxicity analysis revealed higher antiproliferative effect against ovarian carcinoma compared to normal fibroblasts. The biological effect was evaluated in terms of cell adhesion, apoptosis induction, effect on the cell cycle, reactive oxygen species generation, internalization of the complex and proteomic analysis. Unlabelled Image • [Ag(tris(pyrazolyl)methane sulfonate)]n was synthesized and characterized. • X-ray analysis revealed tris(pyrazolyl)methane sulfonate as bridging chelate N3-donor. • The antiproliferative potential of the polymer was characterized. • The polymer shows higher antiproliferative effect in ovarian carcinoma than non-tumour cells. • Antiproliferative effect is due to apoptosis, autophagy and loss of cell adhesion. [ABSTRACT FROM AUTHOR]

Cancer is still one of the deadliest diseases worldwide despite the efforts in its early detection and treatment strategies. However, most chemotherapeutic agents still present side effects in normal tissues and acquired resistance that limit their efficacy. Spiropyrazoline oxindoles might be good alternatives as they have shown antiproliferative activity in human breast and colon cancer cell lines, without eliciting cytotoxicity in healthy cells. However, their potential for ovarian cancer was never tested. In this work, the antiproliferative activity of five spiropyrazoline oxindoles was assessed in ovarian cancer cells A2780 and the biological targets and mechanism of action of the most promising compound evaluated. Compound 1a showed the highest antiproliferative effect, as well as the highest selectivity for A2780 cells compared to healthy fibroblasts. This antiproliferative effect results from the induction of cell death by mitochondria-mediated apoptosis and autophagy. In vitro DNA interaction studies demonstrated that 1a interacts with DNA by groove-binding, without triggering genotoxicity. In addition, 1a showed a strong affinity to bovine serum albumin that might be important for further inclusion in drug delivery platforms. Proteomic studies reinforced 1a role in promoting A2780 endoplasmatic reticulum (ER) stress by destabilizing the correct protein folding which triggers cell death via apoptosis and autophagy. [ABSTRACT FROM AUTHOR]

A 'scorpionate' type precursor bdtbpza = bis(3,5-di- t -butylpyrazol-1-yl)acetate] has been employed to synthesize two mononuclear ZnII and CoII derivatives, namely [Zn(bdtbpza) 2 (H 2 O) 2 ·2.5CH 3 OH·2[(CH 3) 3 C-C 3 H 2 N 2 -C(CH 3) 3 (1) and [Co(bdtbpza) 2 (CH 3 OH) 4 (2) in good yield. Single crystal X-ray diffraction analysis reveals that in 1 , the ZnII atom is tetrahedrally surrounded by a pair of O acetate atoms of two bis(pyrazol-1-yl)acetate units and two water molecules; while in 2 , the CoII atom shows an octahedral environment coordinating a pair of O acetate atoms of two bis(pyrazol-1-yl)acetate units along with four methanol molecules. The EPR spectra of 2 recorded at 77 and 298 K confirmed the tetragonal symmetry of the high spin Co(II). The DFT (Density functional theory) computation is in good agreement with the geometry proposed for compounds 1 and 2. Both the compounds display a high antiproliferative activity against HCT116 (colorectal carcinoma) and A2780 (ovarian carcinoma) cell lines compared to human normal dermal fibroblasts. In the case of A2780 cells, compounds 1 and 2 exhibit IC 50 values that are similar to those described for cisplatin, a widely used chemotherapeutic drug. Exposure of A2780 cells to the IC 50 concentration of each compound led to an increase of the number of apoptotic and autophagic cells. In the case of compound 1 , the accumulation of intracellular ROS (Reactive oxygen species) is responsible for triggering A2780 cell death. Two mononuclear Zn(II) and Co(II) derivatives incorporating 'scorpionate' precursor are afforded and characterized by solid state X-ray diffractometry, spectral and DFT (Density functional theory) studies. The cytotoxic evaluation and anti-proliferative activity alongwith autophagy on human cancer cell lines for both derivatives are discussed. Unlabelled Image • Two octahedral ZnII and CoII complexes with a 'scorpionate' ligand were synthesized. • The complexes were characterized by X-ray, IR, EPR and density function theory. • Antiproliferative activity of both complexes on human cancer cell lines are reported. • Both autophagy and apoptosis may furnish to the reduction of cell viability in A2780 cells. • The Zn(II) complex induces oxidative damages leading to ROS accumulation. [ABSTRACT FROM AUTHOR]