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1.
Cancers (Basel) ; 15(6)2023 Mar 10.
Article in English | MEDLINE | ID: mdl-36980588

ABSTRACT

The chorioallantoic membrane (CAM) assay is an alternative in vivo model that allows for minimally invasive research of cancer biology. Using the CAM assay, we investigated phenotypical and functional characteristics (tumor grade, mitosis rate, tumor budding, hormone receptor (HR) and HER2 status, Ki-67 proliferation index) of two breast cancer cell lines, MCF-7 and MDA-MB-231, which resemble the HR+ (luminal) and triple-negative breast cancer (TNBC) subgroups, respectively. Moreover, the CAM results were directly compared with murine MCF-7- and MDA-MB-231-derived xenografts and human patient TNBC tissue. Known phenotypical and biological features of the aggressive triple-negative breast cancer cell line (MDA-MB-231) were confirmed in the CAM assay, and mouse xenografts. Furthermore, the histomorphological and immunohistochemical variables assessed in the CAM model were similar to those in human patient tumor tissue. Given the confirmation of the classical biological and growth properties of breast cancer cell lines in the CAM model, we suggest this in vivo model to be a reliable alternative test system for breast cancer research to reduce murine animal experiments.

3.
Cancers (Basel) ; 14(1)2021 Dec 28.
Article in English | MEDLINE | ID: mdl-35008299

ABSTRACT

The epithelial-mesenchymal transition (EMT) is associated with tumor aggressiveness and increased invasion, migration, metastasis, angiogenesis, and drug resistance. Although the HCT116 p21-/- cell line is well known for its EMT-associated phenotype, with high Vimentin and low E-cadherin protein levels, the gene signature of this rather intermediate EMT-like cell line has not been determined so far. In this work, we present a robust molecular and bioinformatics analysis, to reveal the associated gene expression profile and its correlation with different types of colorectal cancer tumors. We compared the quantitative signature obtained with the NanoString platform with the expression profiles of colorectal cancer (CRC) Consensus Molecular Subtypes (CMS) as identified, and validated the results in a large independent cohort of human tumor samples. The expression signature derived from the p21-/- cells showed consistent and reliable numbers of upregulated and downregulated genes, as evaluated with two machine learning methods against the four CRC subtypes (i.e., CMS1, 2, 3, and 4). High concordance was found between the upregulated gene signature of HCT116 p21-/- cells and the signature of the CMS4 mesenchymal subtype. At the same time, the upregulated gene signature of the native HCT116 cells was similar to that of CMS1. Using a multivariate Cox regression model to analyze the survival data in the CRC tumor cohort, we selected genes that have a predictive risk power (with a significant gene risk incidence score). A set of genes of the mesenchymal signature was proven to be significantly associated with poor survival, specifically in the CMS4 CRC human cohort. We suggest that the gene signature of HCT116 p21-/- cells could be a suitable metric for mechanistic studies regarding the CMS4 signature and its functional consequences in CRC. Moreover, this model could help to discover the molecular mechanisms of intermediate EMT, which is known to be associated with extraordinarily high stemness and drug resistance.

4.
Angew Chem Int Ed Engl ; 59(38): 16795-16800, 2020 09 14.
Article in English | MEDLINE | ID: mdl-32529715

ABSTRACT

A novel alkynyl phosphane gold(I) complex (trimethylphosphane)(3-(1,3-dimethylxanthine-7-yl)prop-1-yn-1-yl)gold(I) 1 displayed mutiple biological activites including selective proliferation inhibitory, anti-metastatic, and anti-angiogenic effects. The complex also induced effects related to aneuploidy in HCT-116 colon carcinoma cells, which might be mainly ascribed to the dysfunction of mitochondrial bioenergetics and downregulation of glycolysis. Induction of aneuploidy beyond a critical level can provide an effective strategy to target cancer, in particular colorectal tumours with a low tolerance of aneuploidy, and could be of relevance for 1 and other metallodrugs.


Subject(s)
Aneuploidy , Antineoplastic Agents/pharmacology , Colonic Neoplasms/drug therapy , Organogold Compounds/pharmacology , Animals , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Cell Line, Tumor , Cell Proliferation/drug effects , Chickens , Chorioallantoic Membrane/drug effects , Colonic Neoplasms/metabolism , Colonic Neoplasms/pathology , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , HCT116 Cells , Humans , Molecular Structure , Organogold Compounds/chemical synthesis , Organogold Compounds/chemistry , Ovum/drug effects , Reactive Oxygen Species/metabolism , Structure-Activity Relationship
5.
Cell Death Dis ; 11(2): 147, 2020 02 24.
Article in English | MEDLINE | ID: mdl-32094334

ABSTRACT

Epigenetic deregulation remarkably triggers mechanisms associated with tumor aggressiveness like epithelial-mesenchymal transition (EMT). Since EMT is a highly complex, but also reversible event, epigenetic processes such as DNA methylation or chromatin alterations must be involved in its regulation. It was recently described that loss of the cell cycle regulator p21 was associated with a gain in EMT characteristics and an upregulation of the master EMT transcription factor ZEB1. In this study, in silico analysis was performed in combination with different in vitro and in vivo techniques to identify and verify novel epigenetic targets of ZEB1, and to proof the direct transcriptional regulation of SETD1B by ZEB1. The chorioallantoic-membrane assay served as an in vivo model to analyze the ZEB1/SETD1B interaction. Bioinformatical analysis of CRC patient data was used to examine the ZEB1/SETD1B network under clinical conditions and the ZEB1/SETD1B network was modeled under physiological and pathological conditions. Thus, we identified a self-reinforcing loop for ZEB1 expression and found that the SETD1B associated active chromatin mark H3K4me3 was enriched at the ZEB1 promoter in EMT cells. Moreover, clinical evaluation of CRC patient data showed that the simultaneous high expression of ZEB1 and SETD1B was correlated with the worst prognosis. Here we report that the expression of chromatin modifiers is remarkably dysregulated in EMT cells. SETD1B was identified as a new ZEB1 target in vitro and in vivo. Our study demonstrates a novel example of an activator role of ZEB1 for the epigenetic landscape in colorectal tumor cells.


Subject(s)
Colorectal Neoplasms/pathology , Epithelial-Mesenchymal Transition , Zinc Finger E-box-Binding Homeobox 1/genetics , Cell Movement/genetics , Cell Proliferation/genetics , Colorectal Neoplasms/genetics , Epigenesis, Genetic/genetics , Gene Expression Regulation, Neoplastic/genetics , Humans , Up-Regulation
6.
Cell Death Dis ; 10(12): 895, 2019 11 26.
Article in English | MEDLINE | ID: mdl-31772156

ABSTRACT

Colorectal cancer (CRC) is one of the leading cancer-related causes of death worldwide. Despite the improvement of surgical and chemotherapeutic treatments, as of yet, the disease has not been overcome due to metastasis to distant organs. Hence, it is of great relevance to understand the mechanisms responsible for metastasis initiation and progression and to identify novel metastatic markers for a higher chance of preventing the metastatic disease. The Death-associated protein kinase 1 (DAPK1), recently, has been shown to be a potential candidate for regulating metastasis in CRC. Hence, the aim of the study was to investigate the impact of DAPK1 protein on CRC aggressiveness. Using CRISPR/Cas9 technology, we generated DAPK1-deficient HCT116 monoclonal cell lines and characterized their knockout phenotype in vitro and in vivo. We show that loss of DAPK1 implemented changes in growth pattern and enhanced tumor budding in vivo in the chorioallantoic membrane (CAM) model. Further, we observed more tumor cell dissemination into chicken embryo organs and increased invasion capacity using rat brain 3D in vitro model. The novel identified DAPK1-loss gene expression signature showed a stroma typical pattern and was associated with a gained ability for remodeling the extracellular matrix. Finally, we suggest the DAPK1-ERK1 signaling axis being involved in metastatic progression of CRC. Our results highlight DAPK1 as an anti-metastatic player in CRC and suggest DAPK1 as a potential predictive biomarker for this cancer type.


Subject(s)
Colorectal Neoplasms/enzymology , Colorectal Neoplasms/pathology , Death-Associated Protein Kinases/deficiency , Animals , Antigens, Neoplasm/metabolism , CRISPR-Cas Systems/genetics , Cell Adhesion Molecules/metabolism , Cell Proliferation , Chick Embryo , Chorioallantoic Membrane/metabolism , Clone Cells , Colorectal Neoplasms/genetics , Death-Associated Protein Kinases/metabolism , Extracellular Matrix/metabolism , Gene Expression Regulation, Neoplastic , Gene Knockout Techniques , HCT116 Cells , Humans , MAP Kinase Signaling System , Neoplasm Invasiveness , Neoplasm Metastasis , Rats, Wistar , Reproducibility of Results , Spheroids, Cellular/metabolism , Spheroids, Cellular/pathology , Tumor Burden
7.
Cell Death Dis ; 10(6): 379, 2019 05 16.
Article in English | MEDLINE | ID: mdl-31097715

ABSTRACT

Cancer stem cells (CSCs) residing in colorectal cancer tissues have tumorigenic capacity and contribute to chemotherapeutic resistance and disease relapse. It is well known that the survival of colorectal CSCs after 5-fluorouracil (5-FU)-based therapy leads to cancer recurrence. Thus CSCs represent a promising drug target. Here, we designed and synthesized novel hybrid molecules linking 5-FU with the plant-derived compound thymoquinone (TQ) and tested the potential of individual compounds and their combination to eliminate colorectal CSCs. Both, Combi and SARB hybrid showed augmented cytotoxicity against colorectal cancer cells, but were non-toxic to organoids prepared from healthy murine small intestine. NanoString analysis revealed a unique signature of deregulated gene expression in response to the combination of TQ and 5-FU (Combi) and SARB treatment. Importantly, two principle stem cell regulatory pathways WNT/ß-Catenin and PI3K/AKT were found to be downregulated after Combi and hybrid treatment. Furthermore, both treatments strikingly eliminated CD133+ CSC population, accompanying the depleted self-renewal capacity by eradicating long-term propagated 3D tumor cell spheres at sub-toxic doses. In vivo xenografts on chicken eggs of SARB-treated HCT116 cells showed a prominent nuclear ß-Catenin and E-cadherin staining. This was in line with the reduced transcriptional activity of ß-Catenin and diminished cell adhesion under SARB exposure. In contrast to 5-FU, both, Combi and SARB treatment effectively reduced the angiogenic capacity of the remaining resistant tumor cells. Taken together, combination or hybridization of single compounds target simultaneously a broader spectrum of oncogenic pathways leading to an effective eradication of colorectal cancer cells.


Subject(s)
Benzoquinones/pharmacology , Colorectal Neoplasms/genetics , Cytotoxins/pharmacology , Fluorouracil/pharmacology , Neoplastic Stem Cells/drug effects , AC133 Antigen/metabolism , Animals , Benzoquinones/chemistry , Cell Adhesion/drug effects , Chick Embryo , Colorectal Neoplasms/metabolism , Colorectal Neoplasms/pathology , Cytotoxins/chemistry , Fluorouracil/chemistry , Gene Expression Regulation, Neoplastic/drug effects , Humans , Mice , Organoids/drug effects , Xenograft Model Antitumor Assays , beta Catenin/metabolism
8.
Mol Oncol ; 13(6): 1433-1449, 2019 06.
Article in English | MEDLINE | ID: mdl-31069961

ABSTRACT

The high mortality rate of melanoma is broadly associated with its metastatic potential. Tumor cell dissemination is strictly dependent on vascularization; therefore, angiogenesis and lymphangiogenesis play an essential role in metastasis. Hence, a better understanding of the players of tumor vascularization and establishing them as new molecular biomarkers might help to overcome the poor prognosis of melanoma patients. Here, we further characterized a linear murine model of melanoma progression and showed that the aggressiveness of melanoma cells is closely associated with high expression of angiogenic factors, such as Vegfc, Angpt2, and Six1, and that blockade of the vascular endothelial growth factor pathway by the inhibitor axitinib abrogates their tumorigenic potential in vitro and in the in vivo chicken chorioallantoic membrane assay. Furthermore, analysis of The Cancer Genome Atlas data revealed that the expression of the angiogenic factor ANGPT2 (P-value = 0.044) and the lymphangiogenic receptor VEGFR-3 (P-value = 0.002) were independent prognostic factors of overall survival in melanoma patients. Enhanced reduced representation bisulfite sequencing-based methylome profiling revealed for the first time a link between abnormal VEGFC, ANGPT2, and SIX1 gene expression and promoter hypomethylation in melanoma cells. In patients, VEGFC (P-value = 0.031), ANGPT2 (P-value < 0.001), and SIX1 (P-value = 0.009) promoter hypomethylation were independent prognostic factors of shorter overall survival. Hence, our data suggest that these angio- and lymphangiogenesis factors are potential biomarkers of melanoma prognosis. Moreover, these findings strongly support the applicability of our melanoma progression model to unravel new biomarkers for this aggressive human disease.


Subject(s)
Biomarkers, Tumor/metabolism , Lymphangiogenesis/genetics , Melanoma/genetics , Promoter Regions, Genetic/genetics , Animals , Biomarkers, Tumor/genetics , Cell Line, Tumor , Chorioallantoic Membrane/metabolism , DNA Methylation/genetics , Humans , Lymphatic Metastasis/genetics , Lymphatic Metastasis/pathology , Melanoma/metabolism , Melanoma/pathology , Mice , Neovascularization, Pathologic/genetics , Prognosis , Wound Healing/physiology
9.
Cancers (Basel) ; 10(10)2018 Oct 09.
Article in English | MEDLINE | ID: mdl-30304835

ABSTRACT

The oncogenic cytoplasmic p21 contributes to cancer aggressiveness and chemotherapeutic failure. However, the molecular mechanisms remain obscure. Here, we show for the first time that cytoplasmic p21 mediates 5-Fluorouracil (5FU) resistance by shuttling p-Chk2 out of the nucleus to protect the tumor cells from its pro-apoptotic functions. We observed that cytoplasmic p21 levels were up-regulated in 5FU-resistant colorectal cancer cells in vitro and the in vivo Chorioallantoic membrane (CAM) model. Kinase array analysis revealed that p-Chk2 is a key target of cytoplasmic p21. Importantly, cytoplasmic form of p21 mediated by p21T145D transfection diminished p-Chk2-mediated activation of E2F1 and apoptosis induction. Co-immunoprecipitation, immunofluorescence, and proximity ligation assay showed that p21 forms a complex with p-Chk2 under 5FU exposure. Using in silico computer modeling, we suggest that the p21/p-Chk2 interaction hindered the nuclear localization signal of p-Chk2, and therefore, the complex is exported out of the nucleus. These findings unravel a novel mechanism regarding an oncogenic role of p21 in regulation of resistance to 5FU-based chemotherapy. We suggest a possible value of cytoplasmic p21 as a prognosis marker and a therapeutic target in colorectal cancer patients.

10.
J Cell Mol Med ; 22(12): 6238-6248, 2018 12.
Article in English | MEDLINE | ID: mdl-30280520

ABSTRACT

Hepatocellular carcinoma (HCC) is one of the most common causes for cancer-related death worldwide with rapidly increasing incidence and mortality rates. As for other types of cancers, also in HCC cancer stem cells (CSCs) are thought to be responsible for tumour initiation, progression and therapy failure. However, as rare subpopulations of tumour tissue, CSCs are difficult to isolate, thus making the development of suitable and reliable model systems necessary. In our study, we generated HepG2 subclones with enriched CSC potential by application of the spheroid formation method and subsequent single-cell cloning. Analyses in several 2D and 3D cell culture systems as well as a panel of functional assays both in vitro and in vivo revealed that the generated subclones displayed characteristic and sustained features of tumour initiating cells as well as highly aggressive properties related to tumour progression and metastasis. These characteristics could clearly be correlated with the expression of CSC markers that might have prognostic value in the clinical HCC setting. Therefore, we conclude that our CSC enriched HepG2 clones certainly represent suitable model systems to study the role of CSCs during HCC initiation, progression and drug resistance.


Subject(s)
Carcinoma, Hepatocellular/pathology , Liver Neoplasms/pathology , Neoplastic Stem Cells/pathology , Carcinoma, Hepatocellular/genetics , Hep G2 Cells , Humans , Liver Neoplasms/genetics , Neoplastic Stem Cells/metabolism , Xenograft Model Antitumor Assays
11.
ChemMedChem ; 12(3): 226-234, 2017 02 03.
Article in English | MEDLINE | ID: mdl-27973725

ABSTRACT

Colorectal cancer causes 0.5 million deaths each year. To combat this type of cancer the development of new specific drug candidates is urgently needed. In the present work seven novel thymoquinone-artemisinin hybrids with different linkers were synthesized and tested for their in vitro anticancer activity against a panel of various tumor cell lines. The thymoquinone-artesunic acid hybrid 7 a, in which both subunits are connected via an ester bond, was found to be the most active compound and selectively decreased the viability of colorectal cancer cells with an IC50 value of 2.4 µm (HCT116) and 2.8 µm (HT29). Remarkably, hybrid 7 a was up to 20-fold more active than its parent compounds (thymoquinone and artesunic acid), while not affecting nonmalignant colon epithelial HCEC cells (IC50 >100 µm). Moreover, the activity of hybrid 7 a was superior to that of various 1:1 mixtures of thymoquinone and artesunic acid. Furthermore, hybrid 7 a was even more potent against both colon cancer cell lines than the clinically used drug 5-fluorouracil. These results are another excellent proof of the hybridization concept and confirm that the type and length of the linker play a crucial role for the biological activity of a hybrid drug. Besides an increase in reactive oxygen species (ROS), elevated levels of the DNA-damage marker γ-H2AX were observed. Both effects seem to be involved in the molecular mechanism of action for hybrid 7 a in colorectal cancer cells.


Subject(s)
Antineoplastic Agents/chemical synthesis , Artemisinins/chemistry , Benzoquinones/chemistry , Antineoplastic Agents/chemistry , Antineoplastic Agents/toxicity , Cell Survival/drug effects , Colonic Neoplasms/metabolism , Colonic Neoplasms/pathology , HCT116 Cells , HT29 Cells , Histones/metabolism , Humans , Reactive Oxygen Species/metabolism
12.
Chemistry ; 22(52): 18953-18962, 2016 Dec 23.
Article in English | MEDLINE | ID: mdl-27761940

ABSTRACT

Four gold(I) carbene complexes featuring 4-ferrocenyl-substituted imidazol-2-ylidene ligands were investigated for antiproliferative and antivascular properties. They were active against a panel of seven cancer cell lines, including multidrug-resistant ones, with low micromolar or nanomolar IC50 (72 h) values, according to their lipophilicity and cellular uptake. The delocalized lipophilic cationic complexes 8 and 10 acted by increasing the reactive oxygen species in two ways: through a genuine ferrocene effect and by inhibiting the thioredoxin reductase. Both complexes gave rise to a reorganization of the F-actin cytoskeleton in endothelial and melanoma cells, associated with a G1 phase cell cycle arrest and a retarded cell migration. They proved antiangiogenic in tube formation assays with endothelial cells and vascular-disruptive on real blood vessels in the chorioallantoic membrane of chicken eggs. Biscarbene complex 10 was also tolerated well by mice where it led to a volume reduction of xenograft tumors by up to 80 %.


Subject(s)
Antineoplastic Agents/pharmacology , Coordination Complexes/pharmacology , Ferrous Compounds/chemistry , Gold/pharmacology , Metallocenes/chemistry , Reactive Oxygen Species/metabolism , Animals , Antineoplastic Agents/chemistry , Coordination Complexes/chemistry , Gold/chemistry , Mice , Reactive Oxygen Species/chemistry
13.
Dalton Trans ; 45(39): 15390-15398, 2016 Oct 21.
Article in English | MEDLINE | ID: mdl-27603959

ABSTRACT

A general synthesis of novel platinum(ii) complexes bearing two different, cis-oriented, N-heterocyclic carbene (NHC) ligands is presented. Easily accessible cis-[PtII(NHC)(DMSO)] precursor complexes were converted to either cis-[PtII(NHC)2Cl2] complexes such as 5a and 5b, or to novel mixed cis-[PtII(NHC)1(NHC)2Cl2] complexes such as 5c-h by successive introduction of the individual carbene ligands. The 'symmetric' complexes 5a and 5b were also converted to cationic cis-[PtII(NHC)2(PPh3)Cl]+Cl- complexes 8a and 8b. The structures of the ten new complexes, comprising benzylated and alkylated imidazol-2-ylidene ligands, were analysed by 1H, 13C and 195Pt NMR spectroscopy and also by X-ray diffraction for 5a, 5d, 5h, and 8a. The neutral complexes 5 were cytotoxic against a panel of seven human cancer cell lines with IC50 values in the low micromolar range, while the cationic complexes 8 reached even nanomolar IC50 values. Complex 5h carrying the substitution pattern of the natural antitumoral agent Combretastatin A-4 showed a conspicuous specificity for cancer cell lines sensitive to this drug. In electrophoretic mobility shift assays, the cis-biscarbene complexes 5b and 8b led to an unwinding or aggregation of plasmid DNA, while the trans-biscarbene complex 1b showed no such effect.


Subject(s)
Antineoplastic Agents/chemical synthesis , Coordination Complexes/chemical synthesis , Heterocyclic Compounds/chemistry , Methane/analogs & derivatives , Platinum/chemistry , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Cell Line, Tumor , Cell Survival/drug effects , Coordination Complexes/chemistry , Coordination Complexes/pharmacology , Crystallography, X-Ray , Humans , Inhibitory Concentration 50 , Ligands , Methane/chemistry , Molecular Structure
14.
J Inorg Biochem ; 163: 221-228, 2016 10.
Article in English | MEDLINE | ID: mdl-27491634

ABSTRACT

Couples of N-heterocyclic carbene complexes of ruthenium, iridium, platinum, and gold, each differing only in the carbene ligand being either 1,3-dimethylimidazol-2-ylidene (IM) or 1,3-dimethyl-N-boc-O-methylhistidin-2-ylidene (HIS), were assessed for their antiproliferative effect on seven cancer cell lines, their interaction with DNA, their cell cycle interference, and their vascular disrupting properties. In MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] assays only the platinum complexes were cytotoxic at single-digit micromolar IC50 concentrations with the (HIS)Pt complex being on average twice as active as the (IM)Pt complex. The former was highly efficacious against cisplatin-resistant HT-29 colon carcinoma cells where the latter had no effect. Both Pt complexes were accumulated by cancer cells and bound to double-helical DNA equally well. Only the (HIS)Pt complex modified the electrophoretic mobility of circular DNA in vitro due to the HIS ligand causing greater morphological changes to the DNA. Both platinum complexes induced accumulation of 518A2 melanoma cells in G2/M and S phase of the cell cycle. A disruption of blood vessels in the chorioallantoic membrane of fertilized chicken eggs was observed for both platinum complexes and the (IM)gold complex. The (HIS)platinum complex was as active as cisplatin in tumor xenografted mice while being tolerated better. We found that the HIS ligand may augment the cytotoxicity of certain antitumoral metal fragments in two ways: by acting as a transmembrane carrier increasing the cellular accumulation of the complex, and by initiating a pronounced distortion and unwinding of DNA. We identified a new (HIS)platinum complex which was highly cytotoxic against cancer cells including cisplatin-resistant ones.


Subject(s)
Antineoplastic Agents , Gold , Imidazoles , Iridium , Melanoma/drug therapy , Neovascularization, Pathologic/drug therapy , Platinum , Ruthenium , Animals , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Cell Line, Tumor , Chick Embryo , Gold/chemistry , Gold/pharmacology , Humans , Imidazoles/chemical synthesis , Imidazoles/chemistry , Imidazoles/pharmacology , Iridium/chemistry , Iridium/pharmacology , Melanoma/metabolism , Melanoma/pathology , Mice , Neovascularization, Pathologic/metabolism , Neovascularization, Pathologic/pathology , Platinum/chemistry , Platinum/pharmacology , Ruthenium/chemistry , Ruthenium/pharmacology , Xenograft Model Antitumor Assays
15.
Dalton Trans ; 45(33): 13161-8, 2016 Aug 16.
Article in English | MEDLINE | ID: mdl-27334935

ABSTRACT

A rhodium(i) and a ruthenium(ii) complex with a caffeine derived N-heterocyclic carbene (NHC) ligand were biologically investigated as organometallic conjugates consisting of a metal center and a naturally occurring moiety. While the ruthenium(ii) complex was largely inactive, the rhodium(i) NHC complex displayed selective cytotoxicity and significant anti-metastatic and in vivo anti-vascular activities and acted as both a mammalian and an E. coli thioredoxin reductase inhibitor. In HCT-116 cells it increased the reactive oxygen species level, leading to DNA damage, and it induced cell cycle arrest, decreased the mitochondrial membrane potential, and triggered apoptosis. This rhodium(i) NHC derivative thus represents a multi-target compound with promising anti-cancer potential.


Subject(s)
Coordination Complexes/pharmacology , Methane/analogs & derivatives , Rhodium/pharmacology , Animals , Apoptosis/drug effects , Bacteria/drug effects , Bacteria/growth & development , Caffeine/chemistry , Cell Cycle/drug effects , Cell Line, Tumor , Cell Survival/drug effects , Chick Embryo , Chorioallantoic Membrane/blood supply , Chorioallantoic Membrane/drug effects , Coordination Complexes/chemistry , DNA Damage , Humans , Membrane Potential, Mitochondrial/drug effects , Methane/chemistry , Methane/pharmacology , Reactive Oxygen Species/metabolism , Rhodium/chemistry , Wound Healing/drug effects
16.
J Med Chem ; 58(15): 6283-92, 2015 Aug 13.
Article in English | MEDLINE | ID: mdl-26182125

ABSTRACT

Five platinum(II) complexes bearing a (1,3-dibenzyl)imidazol-2-ylidene ligand but different leaving groups trans to it were examined for cytotoxicity, DNA and cell cycle interference, vascular disrupting properties, and nephrotoxicity. The cytotoxicity of complexes 3a-c increased with the steric shielding of their leaving chloride ligand, and complex 3c, featuring two triphenylphosphanes, was the most efficacious, with submicromolar IC50 concentrations. Complexes 3a-c interacted with DNA in electrophoretic mobility shift and ethidium bromide binding assays. The cationic complex 3c did not bind coordinatively to DNA but led to its aggregation, damage that is not amenable to the usual repair mechanisms. Accordingly, it arrested the cell cycle of melanoma cells in G1 phase, whereas cis-dichlorido[(1,3-dibenzyl)imidazol-2-ylidene](dimethyl sulfoxide) platinum(II) 3a induced G2/M phase arrest. Complex 3c also disrupted the blood vessels in the chorioallantoic membrane of fertilized chicken eggs. Ex vivo studies using precision-cut tissue slices suggested the nephrotoxicities of 3a-c to be clinically manageable.


Subject(s)
Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , DNA/drug effects , Methane/analogs & derivatives , Platinum Compounds/chemistry , Platinum Compounds/pharmacology , Cell Line, Tumor , Heterocyclic Compounds/chemistry , Heterocyclic Compounds/pharmacology , Humans , Methane/chemistry
17.
ChemMedChem ; 9(6): 1195-204, 2014 Jun.
Article in English | MEDLINE | ID: mdl-24648184

ABSTRACT

Gold N-heterocyclic carbene (NHC) complexes are an emerging class of anticancer drugs. We present a series of gold(I) biscarbene complexes with NHC ligands derived from the plant metabolite combretastatin A-4 (CA-4) that retain its vascular-disrupting effect, yet address different cellular and protein targets. Unlike CA-4, these complexes did not interfere with tubulin, but with the actin cytoskeleton of endothelial and cancer cells. For the highly metastatic 518A2 melanoma cell line this effect was accompanied by a marked accumulation of cells in the G1 phase of the cell cycle and a suppression of active prometastatic matrix metalloproteinase-2. Despite these mechanistic differences the complexes were as strongly antivascular as CA-4 both in vitro in tube formation assays with human umbilical vein endothelial cells, and in vivo as to blood vessel disruption in the chorioallantoic membrane of chicken eggs. The antiproliferative effect of the new gold biscarbene complexes in a panel of six human cancer cell lines was impressive, with low sub-micromolar IC50 values (72 h) even against CA-4-refractory HT-29 colon and multidrug-resistant MCF-7 breast carcinoma cells. In preliminary studies with a mouse melanoma xenograft model the complexes led to significant decreases in tumor volume while being very well tolerated.


Subject(s)
Antineoplastic Agents/chemistry , Bibenzyls/chemistry , Coordination Complexes/chemistry , Gold/chemistry , Methane/analogs & derivatives , Actin Cytoskeleton/drug effects , Animals , Antineoplastic Agents/pharmacology , Antineoplastic Agents/therapeutic use , Cell Line, Tumor , Cell Proliferation/drug effects , Coordination Complexes/pharmacology , Coordination Complexes/therapeutic use , Drug Resistance, Neoplasm/drug effects , G2 Phase Cell Cycle Checkpoints/drug effects , HT29 Cells , Human Umbilical Vein Endothelial Cells , Humans , MCF-7 Cells , Melanoma/drug therapy , Melanoma/pathology , Methane/chemistry , Mice , Mice, Inbred BALB C , Neovascularization, Physiologic/drug effects , Tubulin/metabolism
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