Also published as: Ai-Qing Ma, Akbarsha MA, Almeida MA, B. Ma, Brimble MA, C. Ma, CS Ma, E. M. Ma, El Amrani MA, El-Magd MA, G.L. Ma, H Ma, Høydal MA, H. Ma, Hashmi MA, Helal MA, Husain MA, J Ma, J. Ma, Jabed MA, Jakupec MA, Jie Ma, Jinfang Ma, Jingru Ma, K. Ma, Kane MA, Khalifa MA, L Ma, L. Ma, Liang Ma, Lima MA, M Ma, M. Ma, Malik MA, Marques MA, Mensah MA, Mroueh MA, Naves MA, Nazif MA, P Ma, P. Ma, PC Ma, Peng-Wei Ma, Q Ma, Qin Ma, Reza Hoda MA, Roberts MA, S Ma, S. Ma, SR Ma, SY Ma, Shaheen MA, Shuangge Ma, Siegler MA, TianâZhu Ma, Trapotsi MA, Vasconcelos MA, W Ma, W. L. Ma, WW Ma, Wanzhi Ma, Wenli Ma, X Ma, X-E Ma, X. Ma, Xianbin Ma, Xiaojie Ma, Xiaoyan Ma, Y Ma, Y. Ma, Z Ma, Zhao-Fu Ma, Zhiyan Ma, Zicheng Ma, de Vasconcelos MA
Oxaliplatin is a platinum analog that can interfere with DNA replication and transcription. Continuous exposure to oxaliplatin results in chemoresistance; however, this mechanism is not well known. In Show more
Oxaliplatin is a platinum analog that can interfere with DNA replication and transcription. Continuous exposure to oxaliplatin results in chemoresistance; however, this mechanism is not well known. In this study, oxaliplatin-resistant (OR) colorectal cancer (CRC) cells of HCT116, HT29, SW480 and SW620 were established by gradually increasing the drug concentration to 2.5 ÎŒM. The inhibitory concentrations of cell growth by 50% (IC 50 ) of oxaliplatin were 4.40â12.7-fold significantly higher in OR CRC cells as compared to their respective parental (PT) CRC cells. Phospho-Akt and phospho-mammalian target of rapamycin (mTOR) decreased in PT CRC cells but was overexpressed in OR CRC cells in response to oxaliplatin. In addition, an oxaliplatin-mediated decrease in phospho-AMP-activated protein kinase (AMPK) in PT CRC cells induced autophagy. Contrastingly, an increased phospho-AMPK in OR CRC cells was accompanied by a decrease in LC3B, further inducing the activity of glycolytic enzymes, such as glucose transporter 1 (GLUT1), 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3 (PFKFB3) and phosphofructokinase 1 (PFK1), to mediate cell survival. Inhibition of AMPK in OR CRC cells induced autophagy through inactivation of Akt/mTOR pathway and a decrease in GLUT1, PFKFB3, and PFK1. Collectively, targeting AMPK may provide solutions to overcome chemoresistance in OR CRC cells and restore chemosensitivity to anticancer drugs. Show less
Summary The treatment of colorectal cancer (CRC) with FOLFOX shows some efficacy, but these tumors quickly develop resistance to this treatment. We have observed increased phosphorylation of AKT1/mTO Show more
Summary The treatment of colorectal cancer (CRC) with FOLFOX shows some efficacy, but these tumors quickly develop resistance to this treatment. We have observed increased phosphorylation of AKT1/mTOR/4EBP1 and levels of p21 in FOLFOX-resistant CRC cells. We have identified a small molecule, NSC49L, that stimulates protein phosphatase 2A (PP2A) activity, downregulates the AKT1/mTOR/4EBP1-axis, and inhibits p21 translation. We have provided evidence that NSC49L- and TRAIL-mediated sensitization is synergistically induced in p21-knockdown CRC cells, which is reversed in p21-overexpressing cells. p21 binds with procaspase 3 and prevents the activation of caspase 3. We have shown that TRAIL induces apoptosis through the activation of caspase 3 by NSC49L-mediated downregulation of p21 translation, and thereby cleavage of procaspase 3 into caspase 3. NSC49L does not affect global protein synthesis. These studies provide a mechanistic understanding of NSC49L as a PP2A agonist, and how its combination with TRAIL sensitizes FOLFOX-resistant CRC cells. Show less
Half-sandwich MII(cym)Cl (cym = η6-p-cymene; M = Ru, Os) complexes of pyridinecarbothioamide (PCA) ligands have demonstrated potential as orally active anticancer agents. In orde Show more
Half-sandwich MII(cym)Cl (cym = η6-p-cymene; M = Ru, Os) complexes of pyridinecarbothioamide (PCA) ligands have demonstrated potential as orally active anticancer agents. In order to investigate the impact of the substitution of the labile chlorido ligand with phosphorous donor ligands on the antiproliferative properties, the triphenylphosphine (PPh3) and 1,3,5-triaza-7-phophaadamantane (pta) analogues were prepared and characterized by spectroscopic techniques and the molecular structures of several complexes were determined by X-diffraction analysis. Interestingly, the molecular structures contained the PCA ligand deprotonated, presumably driven by the reduction in overall charge of the complex. Density Functional Theory (DFT) calculations suggested minor energy differences between the protonated and deprotonated forms. The aqueous stability and the reactivity with the amino acids l-histidine and l-cysteine were investigated by 1H NMR spectroscopy of representative examples. The most potent anticancer agents featured Ru or Os centers and a PPh3 ligand and showed IC50 values in the submicromolar range against four cancer cell lines. This suggests that the antiproliferative activity was mainly dependent on the lipophilic properties of the phosphine ligand with PPh3 having a significantly higher clog P value than pta. Show less
The main purpose of this study was to synthesize a new set of naphthoquinone-based ruthenium(II) arene complexes and to develop an understanding of their mode of action. This study systematically revi Show more
The main purpose of this study was to synthesize a new set of naphthoquinone-based ruthenium(II) arene complexes and to develop an understanding of their mode of action. This study systematically reviews the steps of synthesis, aiming to provide a simplified approach using microwave irradiation. The chemical structures and the physicochemical properties of this novel group of compounds were examined by 1H-NMR and 13C-NMR spectroscopy, X-ray diffractometry, HPLC-MS and supporting DFT calculations. Several aspects of the biological activity were investigated in vitro, including short- and long-term cytotoxicity tests, cellular accumulation studies, detection of reactive oxygen species generation, apoptosis induction and NAD(P)H:quinone oxidoreductase 1 (NQO1) activity as well as cell cycle analysis in A549, CH1/PA-1, and SW480 cancer cells. Furthermore, the DNA interaction ability was studied in a cell-free assay. A positive correlation was found between cytotoxicity, lipophilicity and cellular accumulation of the tested complexes, and the results offer some important insights into the effects of the arene. The most obvious finding to emerge from this study is that the usually very chemosensitive CH1/PA-1 teratocarcinoma cells showed resistance to these phthiocol-based organometallics in comparison to the usually less chemosensitive SW480 colon carcinoma cells, which pilot experiments suggest as being related to NQO1 activity. Show less
Platinum-based anticancer drugs represented by cisplatin play important roles in the treatment of various solid tumors. However, their applications are largely compromised by drug resistance and side Show more
Platinum-based anticancer drugs represented by cisplatin play important roles in the treatment of various solid tumors. However, their applications are largely compromised by drug resistance and side effects. Much effort has been made to circumvent the drug resistance and general toxicity of these drugs. Among multifarious designs, monofunctional platinum(II) complexes with a general formula of [Pt(3A)Cl] + (A: Ammonia or amine) stand out as a class of ânon-traditionalâ anticancer agents hopeful to overcome the defects of current platinum drugs. This review aims to summarize the development of monofunctional platinum(II) complexes in recent years. They are classified into four categories: fluorescent complexes, photoactive complexes, targeted complexes, and miscellaneous complexes. The intention behind the designs is either to visualize the cellular distribution, or to reduce the side effects, or to improve the tumor selectivity, or inhibit the cancer cells through non-DNA targets. The information provided by this review may inspire researchers to conceive more innovative complexes with potent efficacy to shake off the drawbacks of platinum anticancer drugs. Show less
A series of nine RuII arene complexes bearing tridentate naphthoquinone-based N,O,O-ligands was synthesized and characterized. Aqueous stability and their hydrolysis me Show more
A series of nine RuII arene complexes bearing tridentate naphthoquinone-based N,O,O-ligands was synthesized and characterized. Aqueous stability and their hydrolysis mechanism were investigated via UV/vis photometry, HPLC-MS, and density functional theory calculations. Substituents with a positive inductive effect improved their stability at physiological pH (7.4) intensely, whereas substituents such as halogens accelerated hydrolysis and formation of dimeric pyrazolate and hydroxido bridged dimers. The observed cytotoxic profile is unusual, as complexes exhibited much higher cytotoxicity in SW480 colon cancer cells than in the broadly chemo- (incl. platinum-) sensitive CH1/PA-1 teratocarcinoma cells. This activity pattern as well as reduced or slightly enhanced ROS generation and the lack of DNA interactions indicate a mode of action different from established or previously investigated classes of metallodrugs. Show less
Hydroxypyr(id)ones are a pharmaceutically important class of compounds that have shown potential in diverse areas of drug discovery. We investigated the 3-hydroxy-4-pyridones 1a-1c and 3 Show more
Hydroxypyr(id)ones are a pharmaceutically important class of compounds that have shown potential in diverse areas of drug discovery. We investigated the 3-hydroxy-4-pyridones 1a-1c and 3-hydroxy-4-thiopyridones 1d-1f as well as their Ru(η6-p-cymene)Cl complexes 2a-2f, and report here the molecular structures of 1b and 1d as determined by X-ray diffraction analysis. Detailed cell biological investigations revealed potent cytotoxic activity, in particular of the 3-hydroxy-4-thiopyridones 1d-1f, while the Ru complexes of both compound types were less potent, despite still showing antiproliferative activity in the low ΌM range. The compounds did not modulate the cell cycle distribution of cancer cells but were cytostatic in A549 and cytotoxic in NCI-H522 non-small lung cancer cells, among other effects on cancer cells. Show less
Ferroptosis is a form of regulated cell death that is caused by the iron-dependent peroxidation of lipids1,2. The glutathione-dependent lipid hydroperoxidase glutathione peroxidase 4 (GPX4) preve Show more
Ferroptosis is a form of regulated cell death that is caused by the iron-dependent peroxidation of lipids1,2. The glutathione-dependent lipid hydroperoxidase glutathione peroxidase 4 (GPX4) prevents ferroptosis by converting lipid hydroperoxides into non-toxic lipid alcohols3,4. Ferroptosis has previously been implicated in the cell death that underlies several degenerative conditions2, and induction of ferroptosis by the inhibition of GPX4 has emerged as a therapeutic strategy to trigger cancer cell death5. However, sensitivity to GPX4 inhibitors varies greatly across cancer cell lines6, which suggests that additional factors govern resistance to ferroptosis. Here, using a synthetic lethal CRISPR-Cas9 screen, we identify ferroptosis suppressor protein 1 (FSP1) (previously known as apoptosis-inducing factor mitochondrial 2 (AIFM2)) as a potent ferroptosis-resistance factor. Our data indicate that myristoylation recruits FSP1 to the plasma membrane where it functions as an oxidoreductase that reduces coenzyme Q10 (CoQ) (also known as ubiquinone-10), which acts as a lipophilic radical-trapping antioxidant that halts the propagation of lipid peroxides. We further find that FSP1 expression positively correlates with ferroptosis resistance across hundreds of cancer cell lines, and that FSP1 mediates resistance to ferroptosis in lung cancer cells in culture and in mouse tumour xenografts. Thus, our data identify FSP1 as a key component of a non-mitochondrial CoQ antioxidant system that acts in parallel to the canonical glutathione-based GPX4 pathway. These findings define a ferroptosis suppression pathway and indicate that pharmacological inhibition of FSP1 may provide an effective strategy to sensitize cancer cells to ferroptosis-inducing chemotherapeutic agents. Show less
The association of proteins with metals, metalation, is challenging because the tightest binding metals are rarely the correct ones. Inside cells, correct metalation is enabled by controlled bioavaila Show more
The association of proteins with metals, metalation, is challenging because the tightest binding metals are rarely the correct ones. Inside cells, correct metalation is enabled by controlled bioavailability plus extra mechanisms for tricky combinations such as iron and manganese. Show less
Three novel complexes, namely [Nd·L1·HCOO·(H2O)4] (1), [Pr·L1·HCOO·(H2O)4] (2) and [In·L2·Cl·(H2O)2] (3) (L1 = 1,1âbis(5â(pyrazinâ2âyl)â1,2,4âtriazolâ3âyl)methane, L2 = 1,1âbis(5â(pyrazinâ2âyl)â1,2,4â Show more
Three novel complexes, namely [Nd·L1·HCOO·(H2O)4] (1), [Pr·L1·HCOO·(H2O)4] (2) and [In·L2·Cl·(H2O)2] (3) (L1 = 1,1âbis(5â(pyrazinâ2âyl)â1,2,4âtriazolâ3âyl)methane, L2 = 1,1âbis(5â(pyrazinâ2âyl)â1,2,4âtriazolâ3âyl)ketone), were synthesized and characterized. The molecular structures of 1â3 were confirmed using singleâcrystal Xâray diffraction. All three obtained complexes are zeroâdimensional and connected to each other by hydrogen bonds. In 1 and 2 the metal is surrounded by nine donors and 3 has seven coordination sites. The interaction of 1â3 with calf thymus DNA (CTâDNA) was explored using UV absorption spectra and fluorescence spectra. The intrinsic binding constants of 1â3 with CTâDNA are about 1.9 Ă 104, 1.4 Ă 104 and 1.1 Ă 104, respectively. SternâVolmer quenching plots of 1â3 have slopes of 0.1508, 0.134 and 0.1205, respectively. The ability of these complexes to cleave pBR322 plasmid DNA was demonstrated using gel electrophoresis assay. Apoptosis studies of the three novel complexes showed a significant inhibitory effect on HeLa cells. Furthermore, MTT assays were used to evaluate the anticancer activity of the three complexes. The cytotoxicity study indicated that complex 1 possesses a higher inhibitory rate of HeLa cells than the other complexes. Especially, the efficacy of 1 was shown to be the highest for cisplatin at 24 h. A further molecular docking technique was introduced to understand the binding of the complexes toward the target DNA. Show less
New anticancer ruthenium(II/III) complexes [RuCl2(DMSO)2(Hapbim)] (1) and [RuCl3(DMSO) (Hapbim)] (2) (Hapbim = 2-aminophenyl benzimidazole) have been syn Show more
New anticancer ruthenium(II/III) complexes [RuCl2(DMSO)2(Hapbim)] (1) and [RuCl3(DMSO) (Hapbim)] (2) (Hapbim = 2-aminophenyl benzimidazole) have been synthesized and characterized, and their chemotherapeutic potential evaluated. The interaction of the compounds with DNA was studied by both UV-Visible and fluorescence spectroscopies, revealing intercalation of both the Hapbim ligand and the Ru complexes. The in vitro cytotoxicity of the compounds was tested on human breast cancer (MCF7), human colorectal cancer (Caco2), and normal human liver cell lines (THLE-2), with compound (2) the most potent against cancer cells. The cytotoxic effect of (2) is shown to correlate with the ability of the Ru(III) complex to induce apoptosis and to cause cell-cycle arrest in the G2/M phase. Notably, both compounds were inactive in the noncancerous cell line. The anticancer effect of (2) has also been studied in an EAC (Ehrlich Ascites Carcinoma) mouse model. Significantly, the activity of the complex was more pronounced in vivo, with removal of the cancer burden at doses that resulted in only low levels of hepatotoxicity and nephrotoxicity. An apoptosis mechanism was determined by the observation of increased Bax and caspase 3 and decreased Bcl2 expression. Furthermore, (2) decreased oxidative stress and increased the levels of antioxidant enzymes, especially SOD, suggesting the enhancement of normal cell repair. Overall, compound (2) shows great potential as a chemotherapeutic candidate, with promising activity and low levels of side effects. Show less
In this paper, a series of new ruthenium complexes of the general formula [Ru(NS)(dpphpy)(dppb)]PF6 (Ru1-Ru3), where dpphpy = diphenyl-2-pyridylphosphine, NS ligands = 2-thiaz Show more
In this paper, a series of new ruthenium complexes of the general formula [Ru(NS)(dpphpy)(dppb)]PF6 (Ru1-Ru3), where dpphpy = diphenyl-2-pyridylphosphine, NS ligands = 2-thiazoline-2-thiol (tzdt, Ru1), 2-mercaptopyrimidine (pySm, Ru2), and 4,6-diamino-2-mercaptopyrimidine (damp, Ru3), and dppb = 1,4-bis(diphenylphosphino)butane, were synthesized and characterized by elemental analysis, spectroscopic techniques (IR, UV/visible, and 1D and 2D NMR), and X-ray diffraction. In the characterization, the correlation between the phosphorus atoms and their respective aromatic hydrogen atoms of the compounds in the assignment stands outs, by 1H-31P HMBC experiments. The compounds show anticancer activities against A549 (lung) and MDA-MB-231 (breast) cancer cell lines, higher than the clinical drug cisplatin. All of the complexes are more cytotoxic against the cancer cell lines than against the MRC-5 (lung) and MCF-10A (breast) nontumorigenic human cell lines. For A549 tumor cells, cell cycle analysis upon treatment with Ru2 showed that it inhibits the mitotic phase because arrest was observed in the Sub-G1 phase. Additionally, the compound induces cell death by an apoptotic pathway in a dose-dependent manner, according to annexin V-PE assay. The multitargeted character of the compounds was investigated, and the biomolecules were DNA, topoisomerase IB, and proteasome, as well as the fundamental biomolecule in the pharmacokinetics of drugs, human serum albumin. The experimental results indicate that the complexes do not target DNA in the cells. At low concentrations, the compounds showed the ability to partially inhibit the catalytic activity of topoisomerase IB in the process of relaxation of the DNA plasmid. Among the complexes assayed in cultured cells, complex Ru3 was able to diminish the proteasomal chymotrypsin-like activity to a greater extent. Show less
Novel phthiocol-based organometallics with in situ formed tridentate N,O,O-coordination motif were established via three-component microwave assisted one-pot reaction. These complexes exhibited enhanc Show more
Novel phthiocol-based organometallics with in situ formed tridentate N,O,O-coordination motif were established via three-component microwave assisted one-pot reaction. These complexes exhibited enhanced stability in aqueous solution compared to the parental compound KP2048 and showed unexpected cytotoxic behaviour and selectivity in 2D and 3D cell cultures. Show less
A series of 15 piano-stool complexes featuring either a RuII, RhIII or IrIII metal center, a bidentate thiopyridone ligand, and different leaving groups was synthesized. The leaving groups were select Show more
A series of 15 piano-stool complexes featuring either a RuII, RhIII or IrIII metal center, a bidentate thiopyridone ligand, and different leaving groups was synthesized. The leaving groups were selected in order to cover a broad range of different donor atoms. Thus, 1-methylimidazole served as a N-donor, 1,3,5-triaza-7-phosphaadamantane (pta) as a P-donor, and thiourea as a S-donor. Additionally, three complexes featuring different halido leaving groups (Cl, Br, I) were added. Leaving group alterations were carried out with respect to a possible influence on pharmacokinetic and pharmacodynamic parameters, as well as the cytotoxicity of the respective compounds. The complexes were characterized via NMR spectroscopy, X-ray diffraction (where possible), mass spectrometry, and elemental analysis. Cytotoxicity was assessed in 2D cultures of human cancer cell lines by microculture and clonogenic assays as well as in multicellular tumor spheroids. Furthermore, cellular accumulation studies, flow-cytometric apoptosis and ROS assays, DNA plasmid assays, and laser ablation ICP-MS studies for analyzing the distribution in sections of multicellular tumor spheroids were conducted. This work demonstrates the importance of investigating each piano-stool complexes' properties, as the most promising candidates showed advantages over each other in certain tests/assays. Thus, it was not possible to single out one lead compound, but rather a group of complexes with enhanced cytotoxicity and activity. Show less
Left-handed Z-DNA/Z-RNA is bound with high affinity by the Zα domain protein family that includes ADAR (a double-stranded RNA editing enzyme), ZBP1 and viral orthologs regulating innate immunity. Loss Show more
Left-handed Z-DNA/Z-RNA is bound with high affinity by the Zα domain protein family that includes ADAR (a double-stranded RNA editing enzyme), ZBP1 and viral orthologs regulating innate immunity. Loss-of-function mutations in ADAR p150 allow persistent activation of the interferon system by Alu dsRNAs and are causal for Aicardi-GoutiÚres Syndrome. Heterodimers of ADAR and DICER1 regulate the switch from RNA- to protein-centric immunity. Loss of DICER1 function produces age-related macular degeneration, a different type of Alu-mediated disease. The overlap of Z-forming sites with those for the signal recognition particle likely limits invasion of primate genomes by Alu retrotransposons. Show less
Accumulating evidence suggests that aerobic glycolysis is important for colorectal cancer (CRC) development. However, the underlying mechanisms have yet to be elucidated. B7-H3, an immunoregulatory pr Show more
Accumulating evidence suggests that aerobic glycolysis is important for colorectal cancer (CRC) development. However, the underlying mechanisms have yet to be elucidated. B7-H3, an immunoregulatory protein, is broadly overexpressed by multiple tumor types and plays a vital role in tumor progression. In this study, we found that overexpression of B7-H3 effectively increased the rate of glucose consumption and lactate production, whereas knockdown of B7-H3 had the opposite effect. Furthermore, we showed that B7-H3 increased glucose consumption and lactate production by promoting hexokinase 2 (HK2) expression in CRC cells, and we also found that HK2 was a key mediator of B7-H3-induced CRC chemoresistance. Depletion of HK2 expression or treating cells with HK2 inhibitors could reverse the B7-H3-induced increase in aerobic glycolysis and B7-H3-endowed chemoresistance of cancer cells. Moreover, we verified a positive correlation between the expression of B7-H3 and HK2 in tumor tissues of CRC patients. Collectively, our findings suggest that B7-H3 may be a novel regulator of glucose metabolism and chemoresistance via controlling HK2 expression in CRC cells, a result that could help develop B7-H3 as a promising therapeutic target for CRC treatment. Show less
Development of new chemotherapeutic agents to treat microbial infections and recurrent cancers is of pivotal importance. Metal based drugs particularly ruthenium complexes have the uniqueness and desi Show more
Development of new chemotherapeutic agents to treat microbial infections and recurrent cancers is of pivotal importance. Metal based drugs particularly ruthenium complexes have the uniqueness and desired properties that make them suitable candidates for the search of potential chemotherapeutic agents. In this study, two mixed ligand Ru(III) complexes [Ru(Cl)2(SB)(Phen] (RC-1) and [Ru(Cl)2(SB)(Bipy)] (RC-2) were synthesised and characterized by elemental analysis, IR, UV-Vis, 1H, 13C NMR spectroscopic techniques and their molecular structure was confirmed by X-ray crystallography. Antibacterial activity evaluation against two Gram-positive (S. pneumonia and E. faecalis) and four Gram-negative strains (P. aurogenosa, K. pneumoniae, S. enterica, and E. coli) revealed their moderate antibacterial activity with MIC value of â„250âŻÎŒg/mL. Anticancer activity evaluation against a non-small lung cancer cell line (H1299) revealed the tremendous anticancer activity of these complexes which was further validated by DNA binding and docking results. DNA binding profile of the complexes studied by UV-Visible and fluorescence spectroscopy showed an intercalative binding mode with CT-DNA and an intrinsic binding constant in the range of 3.481-1.015ĂâŻ105âŻM-1. Both the complexes were also found to exert weak toxicity to human erythrocytes by haemolytic assay compared to cisplatin. Potential of these complexes as anticancer agents will be further delineated by in vivo studies. Show less
Benzoylthiourea derivatives feature several donor atoms capable of coordinating to metal centers. We report here a series of Ru(η6 -p-cymene) complexes employing benzoylthiourea derivatives Show more
Benzoylthiourea derivatives feature several donor atoms capable of coordinating to metal centers. We report here a series of Ru(η6 -p-cymene) complexes employing benzoylthiourea derivatives as ligands. Such ligands often coordinate to metal centers through their S and O donor atoms. We isolated complexes where the ligands were mono- or bidentately coordinated to Ru involving the S donor atom and surprisingly in bidentate coordination mode a deprotonated thiourea nitrogen resulting in a 4-membered ring structure around the metal center. DFT calculations were used to explain the differences in coordination behavior. These were complemented by stability studies and biological investigations of the compounds as anticancer agents. Several of the synthesized derivatives exhibited significant cell growth inhibitory activity, with the complexes featuring bidentate ligands being more potent than their monodentate counterparts. This can be explained by the higher stability of the former under the conditions employed in cell culture assays. Show less
The use of ruthenium complexes as chemotherapeutic agents has been recently explored as one of the alternatives to conventional treatments. In the present study, two Ru(ii) polypyridyl complexes were Show more
The use of ruthenium complexes as chemotherapeutic agents has been recently explored as one of the alternatives to conventional treatments. In the present study, two Ru(ii) polypyridyl complexes were synthesized and characterized: a strained [Ru(bipy)2(BC)]Cl2 (complex 1) where [bipy = 2,2'-bipyridine and BC = bathocuproine] along with the unstrained control [Ru(bipy)2(phen)]Cl2 (complex 2) where [phen = 1,10-phenanthroline]. The photophysical and photochemical analyses proved that unlike the photostable complex 2, complex 1 ejected both bipy and BC ligands at a ratio of 3â:â1 respectively. Results showed that the activity of complex 1 was significantly enhanced upon photoactivation. The response was however particularly significant in B16-F10 melanoma cells where phototoxicity index (PI = IC50 dark/IC50 light) was >900. When compared to cisplatin, the photoproducts were more potent against all tested cell lines, implying that the complex acquired significant chemotherapeutic potential upon irradiation. Cellular uptake of complex 1 and the free BC ligand were found to be significantly facilitated as evidenced by 400-600 fold increase in concentration of the compounds inside the cells relative to the extracellular culture medium. Complex 2 exhibited 35 times lower cellular concentration relative to complex 1. Flow cytometry and plasmid DNA gel electrophoresis measurements showed that complex 1 interacts with DNA inducing apoptosis in the dark and either late-apoptosis or necrosis upon irradiation. These findings corroborate the importance of lipophilic ligands such as BC to enhance uptake and subsequently improve the photochemotherapy potential of Ru(ii) polypyridyl complexes. Show less
The triple-negative breast cancer subtype (TNBC) is highly aggressive and metastatic and corresponds to 15-20% of diagnosed cases. TNBC treatment is hampered, because these cells usually do not respon Show more
The triple-negative breast cancer subtype (TNBC) is highly aggressive and metastatic and corresponds to 15-20% of diagnosed cases. TNBC treatment is hampered, because these cells usually do not respond to hormonal therapy, and they develop resistance to chemotherapeutic drugs. On the other hand, the severe side effects of cisplatin represent an obstacle for its clinical use. Ruthenium (Ru)-based complexes have emerged as promising antitumor and antimetastatic substitutes for cisplatin. In this study, we demonstrated the effects of a Ru/biphosphine complex, containing gallic acid (GA) as a ligand, [Ru(GA)(dppe)2]PF6, hereafter called Ru(GA), on a TNBC cell line, and compared them to the effects in a nontumor breast cell line. Ru(GA) complex presented selective cytotoxicity against TNBC over nontumor cells, inhibited its migration and invasion, and induced apoptosis. These effects were associated with the increased amount of transferrin receptors (TfR) on tumor cells, compared to nontumor ones. Silencing of TfR decreased Ru(GA) effects on TNBC cells, demonstrating that these receptors were at least partially responsible for Ru(GA) delivery into tumor cells. The Ru(GA) compound must be further studied in different in vivo assays in order to investigate its antitumor properties and its toxicity in complex biological systems. Show less
Two new complexes of Ru(II) with mixed ligands were prepared: [Ru(bpy)2smp](PF6) (1) and [Ru(phen)2smp](PF6) (2), in which smp = sulfamethoxyp Show more
Two new complexes of Ru(II) with mixed ligands were prepared: [Ru(bpy)2smp](PF6) (1) and [Ru(phen)2smp](PF6) (2), in which smp = sulfamethoxypyridazine; bpy = 2,2'-bipyridine; phen = 1,10-phenanthroline. The complexes have been characterized by elemental and conductivity analyses; infrared, NMR, and electrospray ionization mass spectroscopies; and X-ray diffraction of single crystal. Structural analyses reveal a distorted octahedral geometry around Ru(II) that is bound to two bpy (in 1) or two phen (in 2) via their two heterocyclic nitrogens and to two nitrogen atoms from sulfamethoxypyridazine-one of the methoxypyridazine ring and the sulfonamidic nitrogen, which is deprotonated. Both complexes inhibit the growth of chronic myelogenous leukemia cells. The interaction of the complexes with bovine serum albumin and DNA is described. DNA footprinting using an oligonucleotide as substrate showed the complexes' preference for thymine base rich sites. It is worth notifying that the complexes interact with the Src homology SH3 domain of the Abl tyrosine kinase protein. Abl protein is involved in signal transduction and implicated in the development of chronic myelogenous leukemia. Nuclear magnetic resonance (NMR) studies of the interaction of complex 2 with the Abl-SH3 domain showed that the most affected residues were T79, G97, W99, and Y115. Show less
Fine-tuning of the properties of a recently reported 1,3-indandione-based organoruthenium complex is attempted to optimize the stability under physiological conditions. Previous work has shown its cap Show more
Fine-tuning of the properties of a recently reported 1,3-indandione-based organoruthenium complex is attempted to optimize the stability under physiological conditions. Previous work has shown its capacity of inhibiting topoisomerase IIα; however, fast aquation leads to undesired reactions and ligand cleavage in the blood stream before the tumor tissue is reached. Exchange of the chlorido ligand for six different N-donor ligands resulted in new analogs that were stable at pH 7.4 and 8.5. Only a lowered pH level, as encountered in the extracellular space of the tumor tissue, was capable of aquating the complexes. The 50% inhibitory concentration (IC50) values in three human cancer cell lines differed only slightly, and their dependence on the utilized leaving group was smaller than what would be expected from their differences in cellular accumulation, but in accordance with the very minor variation revealed in measurements of the complexes' lipophilicity. Show less
Abstract Significance: Mitochondria are the energetic, metabolic, redox, and information signaling centers of the cell. Substrate pressure, mitochondrial network dynamics, and cristae morphology Show more
Abstract Significance: Mitochondria are the energetic, metabolic, redox, and information signaling centers of the cell. Substrate pressure, mitochondrial network dynamics, and cristae morphology state are integrated by the protonmotive force Î p or its potential component, ΠΚ , which are attenuated by proton backflux into the matrix, termed uncoupling. The mitochondrial uncoupling proteins (UCP1â5) play an eminent role in the regulation of each of the mentioned aspects, being involved in numerous physiological events including redox signaling. Recent Advances: UCP2 structure, including purine nucleotide and fatty acid (FA) binding sites, strongly support the FA cycling mechanism: UCP2 expels FA anions, whereas uncoupling is achieved by the membrane backflux of protonated FA. Nascent FAs, cleaved by phospholipases, are preferential. The resulting Î p dissipation decreases superoxide formation dependent on Î p . UCP-mediated antioxidant protection and its impairment are expected to play a major role in cell physiology and pathology. Moreover, UCP2-mediated aspartate, oxaloacetate, and malate antiport with phosphate is expected to alter metabolism of cancer cells. Critical Issues: A wide range of UCP antioxidant effects and participations in redox signaling have been reported; however, mechanisms of UCP activation are still debated. Switching off/on the UCP2 protonophoretic function might serve as redox signaling either by employing/releasing the extra capacity of cell antioxidant systems or by directly increasing/decreasing mitochondrial superoxide sources. Rapid UCP2 degradation, FA levels, elevation of purine nucleotides, decreased Mg 2+ , or increased pyruvate accumulation may initiate UCP-mediated redox signaling. Future Directions: Issues such as UCP2 participation in glucose sensing, neuronal (synaptic) function, and immune cell activation should be elucidated. Antioxid. Redox Signal. 29, 667â714. Show less
Highly ordered interactions between immune and metabolic responses are evolutionarily conserved and paramount for tissue and organismal health. Disruption of these interactions underlies the emergence Show more
Highly ordered interactions between immune and metabolic responses are evolutionarily conserved and paramount for tissue and organismal health. Disruption of these interactions underlies the emergence of many pathologies, particularly chronic non-communicable diseases such as obesity and diabetes. Here, we examine decades of research identifying the complex immunometabolic signaling networks and the cellular and molecular events that occur in the setting of altered nutrient and energy exposures and offer a historical perspective. Furthermore, we describe recent advances such as the discovery that a broad complement of immune cells play a role in immunometabolism and the emerging evidence that nutrients and metabolites modulate inflammatory pathways. Lastly, we discuss how this work may eventually lead to tangible therapeutic advancements to promote health. Show less
Mitochondrial Ca 2+ uptake plays a pivotal role both in cell energy balance and in cell fate determination. Studies on the role of mitochondrial Ca 2+ signaling in pathophysiology have been favored Show more
Mitochondrial Ca 2+ uptake plays a pivotal role both in cell energy balance and in cell fate determination. Studies on the role of mitochondrial Ca 2+ signaling in pathophysiology have been favored by the identification of the genes encoding the mitochondrial calcium uniporter (MCU) and its regulatory subunits. Thus, research carried on in the last years on one hand has determined the structure of the MCU complex and its regulation, on the other has uncovered the consequences of dysregulated mitochondrial Ca 2+ signaling in cell and tissue homeostasis. Whether mitochondrial Ca 2+ uptake can be exploited as a weapon to counteract cancer progression is debated. In this review, we summarize recent research on the molecular structure of the MCU, the regulatory mechanisms that control its activity and its relevance in pathophysiology, focusing in particular on its role in cancer progression. Show less
Within this work we aimed to improve the pharmacodynamics and toxicity profile of organoruthenium and -rhodium complexes which had previously been found to be highly potent in vitro but showed unselec Show more
Within this work we aimed to improve the pharmacodynamics and toxicity profile of organoruthenium and -rhodium complexes which had previously been found to be highly potent in vitro but showed unselective activity in vivo. Different organometallic complexes were attached to a degradable poly(organo)phosphazene macromolecule, prepared via controlled polymerization techniques. The conjugation to hydrophilic polymers was designed to increase the aqueous solubility of the typically poorly soluble metal-based half-sandwich compounds with the aim of a controlled, pH-triggered release of the active metallodrug. The synthesized conjugates and their characteristics have been thoroughly studied by means of 31P NMR and UV-Vis spectroscopy, ICP-MS analyses and SEC coupled to ICP-MS. In order to assess their potential as possible anticancer drug candidates, the complexes, as well as their respective macromolecular prodrug formulations were tested against three different cancer cell lines in cell culture. Subsequently, the anticancer activity and organ distribution of the poly(organo)phosphazene drug conjugates were explored in vivo in mice bearing CT-26 colon carcinoma. Our investigations revealed a beneficial influence of this macromolecular prodrug by a significant reduction of adverse effects compared to the free metallodrugs. Show less