RESUMEN
Organometallic η6-arene ruthenium(II) complexes with 3-chloro-6-(1H-pyrazol-1-yl)pyridazine (Ru1, Ru2, and Ru5) and 3-chloro-6-(3,5-dimethyl-1H-pyrazol-1-yl)pyridazine (Ru3-4) N,N' heterocyclic and η6-arene (cymene (Ru1-4) or toluene (Ru 5)) have been synthesized. The ruthenium(II) complexes have common "three-legged piano-stool" pseudo-octahedral structures known for half-sandwich complexes. Evolution of their UV-Visible absorption spectra in PBS buffer or DMSO over 24 h confirmed their good solvolysis stability. Titrations of the complexes with the calf thymus DNA (CT-DNA) were monitored using UV-Visible absorption and fluorescence spectroscopies. The complexes interact moderately with CT-DNA and their binding constants are in the order of 104 M-1. Competitive binding of the complexes to a DNA-Hoechst 33,258 depicted competitive displacement of Hoechst from DNA's minor grooves. These complexes bind to glutathione forming GSH-adducts through S coordination by replacement of a halide, with the iodo-analogues having higher binding constants than the chloro-complexes. Cyclic voltammograms of the complexes exhibited one electron-transfer quasi-reversible process. Trends in the molecular docking data of Ru1-5/DNA were similar to those for DNA binding constants. Of the five, only Ru1, Ru3 and Ru5 showed some activity (moderate) against the MCF-7 breast cancer cells with IC50 values in the range of 59.2-39.9 for which Ru5 was the most active. However, the more difficult-to-treat cell line, MDA-MB 231 cell was recalcitrant to the treatment by these complexes.
Asunto(s)
Antineoplásicos , Complejos de Coordinación , ADN , Glutatión , Rutenio , ADN/química , ADN/metabolismo , Humanos , Rutenio/química , Ligandos , Complejos de Coordinación/química , Complejos de Coordinación/farmacología , Complejos de Coordinación/síntesis química , Antineoplásicos/farmacología , Antineoplásicos/química , Antineoplásicos/síntesis química , Glutatión/química , Glutatión/metabolismo , Bovinos , Pirazoles/química , Pirazoles/farmacología , Pirazoles/síntesis química , Animales , Estructura Molecular , Ensayos de Selección de Medicamentos Antitumorales , Proliferación Celular/efectos de los fármacos , Células MCF-7 , Línea Celular TumoralRESUMEN
Cell stiffness and T-box transcription factor 3 (TBX3) expression have been identified as biomarkers of melanoma metastasis in 2D environments. This study aimed to determine how mechanical and biochemical properties of melanoma cells change during cluster formation in 3D environments. Vertical growth phase (VGP) and metastatic (MET) melanoma cells were embedded in 3D collagen matrices of 2 and 4 mg/ml collagen concentrations, representing low and high matrix stiffness. Mitochondrial fluctuation, intracellular stiffness, and TBX3 expression were quantified before and during cluster formation. In isolated cells, mitochondrial fluctuation decreased and intracellular stiffness increased with increase in disease stage from VGP to MET and increased matrix stiffness. TBX3 was highly expressed in soft matrices but diminished in stiff matrices for VGP and MET cells. Cluster formation of VGP cells was excessive in soft matrices but limited in stiff matrices, whereas for MET cells it was limited in soft and stiff matrices. In soft matrices, VGP cells did not change the intracellular properties, whereas MET cells exhibited increased mitochondrial fluctuation and decreased TBX3 expression. In stiff matrices, mitochondrial fluctuation and TBX3 expression increased in VGP and MET, and intracellular stiffness increased in VGP but decreased in MET cells. The findings suggest that soft extracellular environments are more favourable for tumour growth, and high TBX3 levels mediate collective cell migration and tumour growth in the earlier VGP disease stage but play a lesser role in the later metastatic stage of melanoma.
Asunto(s)
Melanoma , Humanos , Línea Celular Tumoral , Melanoma/patología , Colágeno , Movimiento Celular , Proteínas de Dominio T Box/genética , Proteínas de Dominio T Box/metabolismoRESUMEN
The increased success of small metal-containing molecules as pharmaceutical agents has prompted investigations into the pharmacological activity of a different class of metal-based compounds; supramolecular coordination complexes (SCCs). Such complexes have been extensively investigated for their anticancer activity, with many displaying activities comparable or superior to available clinical chemotherapeutic drugs. Here, we evaluated a series of quinoline-containing binuclear complexes and metallarectangles for their inâ vitro anticancer activity in the hormone receptor positive MCF-7 and triple negative MDA-MB-231 breast cancer cell lines. The preliminary cytotoxic screen, in the MCF-7â cell line, revealed that the ligand (7-chloro-4-(pyridin-4-yl)quinoline, L) and metallarectangle [{Ir(µ-Cl)(Cp*)}4 (µ-L)2 ](OTf)4 display superior activity to cisplatin, while [{Ru(p-cymene)}4 (µ-η2 -η2 -C2 O4 )2 (µ-L)2 ](OTf)4 was more potent than cisplatin in the triple-negative MDA-MD-231â cell line. Upon evaluation in a multidose screen, ligand L and metallarectangle [{Ir(µ-Cl)(Cp*)}4 (µ-L)2 ](OTf)4 displayed antiproliferative activity almost two-fold greater than cisplatin in the MCF-7â cell line, while [{Ru(p-cymene)}4 (µ-η2 -η2 -C2 O4 )2 (µ-L)2 ](OTf)4 was over two-times more active than cisplatin in the MDA-MB-231â cell line. Additionally, using the non-tumorigenic MCF-12â A breast epithelial cell line, the compounds demonstrate increased selectivity toward breast cancer cells over non-tumorigenic cells. Furthermore, investigations into the interactions of ligand L and selected complexes with calf thymus DNA (CT-DNA) and bovine serum albumin (BSA) indicate favourable binding.
Asunto(s)
Antineoplásicos , Neoplasias de la Mama , Complejos de Coordinación , Quinolinas , Rutenio , Humanos , Femenino , Cisplatino , Simulación del Acoplamiento Molecular , Albúmina Sérica Bovina/química , Ligandos , Complejos de Coordinación/química , Antineoplásicos/química , Células MCF-7 , ADN/química , Línea Celular Tumoral , Rutenio/farmacología , Rutenio/químicaRESUMEN
The formation of membrane protrusions during migration is reliant upon the cells' cytoskeletal structure and stiffness. It has been reported that actin disruption blocks protrusion and decreases cell stiffness whereas microtubule disruption blocks protrusion but increases stiffness in several cell types. In melanoma, cell migration is of concern as this cancer spreads unusually rapidly during early tumour development. The aim of this study was to characterise motility, structural properties and stiffness of human melanoma cells at radial growth phase (RGP), vertical growth phase (VGP), and metastatic stage (MET) in two-dimensional in vitro environments. Wound assays, western blotting and mitochondrial particle tracking were used to assess cell migration, cytoskeletal content and intracellular fluidity. Our results indicate that cell motility increase with increasing disease stage. Despite their different motility, RGP and VGP cells exhibit similar fluidity, actin and tubulin levels. MET cells, however, display increased fluidity which was associated with increased actin and tubulin content. Our findings demonstrate an interplay between actin and microtubule activity and their role in increasing motility of cells while minimizing cell stiffness at advanced disease stage. In earlier disease stages, cell stiffness may however not serve as an indicator of migratory capabilities.
Asunto(s)
Actinas/metabolismo , Citoesqueleto/metabolismo , Melanoma/metabolismo , Melanoma/patología , Tubulina (Proteína)/metabolismo , Línea Celular Tumoral , Movimiento Celular , Proliferación Celular , Forma de la Célula , Progresión de la Enfermedad , Fluorescencia , Humanos , Mitocondrias/metabolismo , Metástasis de la NeoplasiaRESUMEN
Plant-derived compounds and/or extracts have proven to be beneficial for the treatment of a broad spectrum of cancers with minimal side effects. In this study, we investigated whether a crude acetone extract of Momordica balsamina (MBE) can interfere with the metastatic ability of HT-29 colorectal cancer (CRC) cells. The phytochemical composition of MBE was determined by ultra-performance liquid chromatography and cytotoxic effects by the MTT and acridine orange/ethidium bromide staining assays. The effect of MBE on the formation of reactive oxygen species was assessed using the DCFH2 -DA assay. Wound healing assay, transwell cell invasion assay, cell adhesion assay, and the extracellular matrix-cell adhesion array were used to assess the antimetastatic effects of MBE. The effect of MBE on the expression of TNF-α, NF-κB, TIMP-3, MMP-2, and MMP-9 was assessed by western blot analysis. Our results showed that MBE consists of a mixture of compounds without a known anticancer activity in CRC and exhibits cytotoxicity against HT-29 cells. MBE also suppressed reactive oxygen species formation, cell invasion, cell migration, and cell adhesion. The reduction of cell invasion was associated with the downregulation of TNF-α, NF-κB, MMP2, and MMP9 and upregulation of TIMP-3 proteins. We concluded that MBE inhibits the metastatic ability of HT-29 CRC cells in vitro.
Asunto(s)
Neoplasias del Colon , Momordica , Acetona , Línea Celular Tumoral , Movimiento Celular , Proliferación Celular , Neoplasias del Colon/tratamiento farmacológico , Células HT29 , Humanos , Extractos Vegetales/farmacologíaRESUMEN
As the global incidences of colorectal cancer rises, there is a growing importance in understanding the interaction between external factors, such as common infections, on the initiation and progression of this disease. While certain helminth infections have been shown to alter the severity and risk of developing colitis-associated colorectal cancer, whether these parasites can directly affect colorectal cancer progression is unknown. Here, we made use of murine and human colorectal cancer cell lines to demonstrate that exposure to antigens derived from the gastrointestinal nematode Heligmosomoides polygyrus significantly reduced colorectal cancer cell proliferation in vitro. Using a range of approaches, we demonstrate that antigen-dependent reductions in cancer cell proliferation and viability are associated with increased expression of the critical cell cycle regulators p53 and p21. Interestingly, H. polygyrus-derived antigens significantly increased murine colorectal cancer cell migration, which was associated with an increased expression of the adherens junction protein ß-catenin, whereas the opposite was true for human colorectal cancer cells. Together, these findings demonstrate that antigens derived from a gastrointestinal nematode can significantly alter colorectal cancer cell behavior. Further in-depth analysis may reveal novel candidates for targeting and treating late-stage cancer.
Asunto(s)
Antígenos Helmínticos/farmacología , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/patología , Transición Epitelial-Mesenquimal/efectos de los fármacos , Nematospiroides dubius/inmunología , Animales , Antígenos Helmínticos/inmunología , Línea Celular Tumoral , Movimiento Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Neoplasias Colorrectales/genética , Inhibidor p21 de las Quinasas Dependientes de la Ciclina/metabolismo , Transición Epitelial-Mesenquimal/fisiología , Células HCT116 , Humanos , Masculino , Ratones Endogámicos C57BL , Nematospiroides dubius/metabolismo , Schistosoma mansoni/inmunología , Esquistosomiasis mansoni/inmunología , Especificidad de la Especie , Proteína p53 Supresora de Tumor/metabolismo , beta Catenina/metabolismoRESUMEN
Globally, breast cancer is the most common malignancy in women and the second most common cause of cancer-related death among women. There is therefore a need to identify more efficacious therapies for this neoplasm. Galenia africana (Kraalbos) is a perennial shrub found in Southern Africa and is used by the indigenous people to treat various ailments. There has therefore been much interest to establish the scientific basis for the medicinal properties of Kraalbos. This study aimed to investigate and characterise the anti-cancer activity of an ethanolic extract of Kraalbos leaves, KB2, against oestrogen receptor positive (MCF-7) and triple negative (MDA-MB-231) breast cancer cells. LC-MS/MS analyses identified the phytochemicals 7'-hydroxyflavanone, 5',7'-dihydroxyflavanone, 2',4'-dihydroxydihydrochalcone and 2',4'-dihydroxychalcone in KB2. KB2 exhibited an IC50 of 114 µg/ml and 130.5 µg/ml in MCF-7 and MDA-MB-231 cells respectively, selectively inhibited their long-term survival and reduced their migration which correlated with a decrease in EMT markers. It induced oxidative stress (ROS), DNA damage (increased levels of γ-H2AX), and triggered cell cycle arrests in MCF-7 and MDA-MB-231 cells. Importantly, KB2 activated intrinsic (cleaved caspase 9) and extrinsic (cleaved caspase 8) apoptosis, necroptosis (p-RIP3 and the downstream target of the necrosome, pMLKL) and autophagy (LC3II). Co-treatment of the breast cancer cells with KB2 and the autophagy inhibitor bafilomycin A1 resulted in a significant increase in cell viability which suggests that KB2 induced autophagy is a cell death mechanism.
RESUMEN
5-Fluorouracil (5-FU) is a chemotherapeutic agent used to treat a variety of gastric cancers including oesophageal squamous cell carcinoma (OSCC), for which the 5-year mortality rate exceeds 85%. Our study investigated the effects of metformin, an antidiabetic drug with established anti-cancer activity, in combination with 5-FU as a novel chemotherapy strategy, using the OSCC cell lines, WHCO1 and WHCO5. Our results indicate that metformin treatment induces significant resistance to 5-FU in WHCO1 and WHCO5 cells, by more than five- and sixfolds, respectively, as assessed by MTT assay. We show that this is due to global alterations in nucleotide metabolism, including elevated expression of thymidylate synthase and thymidine kinase 1 (established 5-FU resistance mechanisms), which likely result in an increase in intracellular dTTP pools and a "dilution" of 5-FU anabolites. Metformin treatment also increases deoxycytidine kinase (dCK) expression and, as the chemotherapeutic agent gemcitabine relies on dCK for its efficient activity, we speculated that metformin would enhance the sensitivity of OSCC cells to gemcitabine. Indeed we show that metformin pre-treatment greatly increases gemcitabine toxicity and DNA fragmentation in comparison to gemcitabine alone. Taken together, our findings show that metformin alters nucleotide metabolism in OSCC cells and while responsible for inducing resistance to 5-FU, it conversely increases sensitivity to gemcitabine, thereby highlighting metformin and gemcitabine as a potentially novel combination therapy for OSCC.
Asunto(s)
Carcinoma de Células Escamosas/tratamiento farmacológico , Desoxicitidina/análogos & derivados , Resistencia a Antineoplásicos , Neoplasias Esofágicas/tratamiento farmacológico , Fluorouracilo/administración & dosificación , Metformina/administración & dosificación , Nucleótidos de Timina/metabolismo , Animales , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Carcinoma de Células Escamosas/genética , Línea Celular Tumoral , Desoxicitidina/administración & dosificación , Desoxicitidina/farmacología , Desoxicitidina Quinasa/metabolismo , Resistencia a Antineoplásicos/efectos de los fármacos , Sinergismo Farmacológico , Neoplasias Esofágicas/genética , Carcinoma de Células Escamosas de Esófago , Fluorouracilo/farmacología , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Metformina/efectos adversos , Ratones , Timidina Quinasa/genética , Timidilato Sintasa/genética , Regulación hacia Arriba , Ensayos Antitumor por Modelo de Xenoinjerto , GemcitabinaRESUMEN
A series of bidentate salicylaldimine ligands was prepared and reacted with either [RuCl(µ-Cl)(p-cymene)]2, [RhCl(µ-Cl)(Cp*)]2 or [IrCl(µ-Cl)(Cp*)]2. All of the compounds were characterised using an array of spectroscopic and analytical techniques, namely, nuclear magnetic resonance (NMR) spectroscopy, infrared (IR) spectroscopy and mass spectrometry. Single crystal X-ray diffraction (XRD) was used to confirm the bidentate coordination mode of the salicylaldimine ligand to the metal centre. The platinum group metal (PGM) complexes were screened against the MCF7 breast cancer cell line. The ruthenium and iridium salicylaldimine complexes showed comparable or greater cytotoxicity than cisplatin against the MCF7 cancer cells, as well as greater cytotoxicity than their rhodium counterparts. Three of the salicylaldimine complexes showed potent activity in the range 18-21 µM. Two of these complexes had a greater affinity for cancerous cells than for CHO non-cancerous cells (SI > 4). Preliminary mechanistic studies suggest that the ruthenium complexes undergo solvation prior to 5'-GMP binding, whereas the iridium complexes were inert to the solvation process.
Asunto(s)
ADN/química , Iridio/química , Compuestos Organometálicos/química , Rodio/química , Rutenio/química , Cristalografía por Rayos X , Humanos , Células MCF-7 , Análisis Espectral/métodosRESUMEN
Genomic instability is a major hallmark of cancer. To maintain genomic integrity, cells are equipped with dedicated sensors to monitor DNA repair or to force damaged cells into death programs. The tumor suppressor p53 is central in this process. Here, we report that the ubiquitous transcription factor Upstream Stimulatory factor 1 (USF1) coordinates p53 function in making proper cell fate decisions. USF1 stabilizes the p53 protein and promotes a transient cell cycle arrest, in the presence of DNA damage. Thus, cell proliferation is maintained inappropriately in Usf1 KO mice and in USF1-deficient melanoma cells challenged by genotoxic stress. We further demonstrate that the loss of USF1 compromises p53 stability by enhancing p53-MDM2 complex formation and MDM2-mediated degradation of p53. In USF1-deficient cells, the level of p53 can be restored by the re-expression of full-length USF1 protein similarly to what is observed using Nutlin-3, a specific inhibitor that prevents p53-MDM2 interaction. Consistent with a new function for USF1, a USF1 truncated protein lacking its DNA-binding and transactivation domains can also restore the induction and activity of p53. These findings establish that p53 function requires the ubiquitous stress sensor USF1 for appropriate cell fate decisions in response to DNA-damage. They underscore the new role of USF1 and give new clues of how p53 loss of function can occur in any cell type. Finally, these findings are of clinical relevance because they provide new therapeutic prospects in stabilizing and reactivating the p53 pathway.
Asunto(s)
Diferenciación Celular , Neoplasias/genética , Proteína p53 Supresora de Tumor/metabolismo , Factores Estimuladores hacia 5'/metabolismo , Animales , Apoptosis/genética , Línea Celular Tumoral , Linaje de la Célula , Proliferación Celular , Daño del ADN/genética , Inestabilidad Genómica , Humanos , Ratones , Mapas de Interacción de Proteínas/genética , Proteínas Proto-Oncogénicas c-mdm2/metabolismo , Proteína p53 Supresora de Tumor/genética , Factores Estimuladores hacia 5'/genéticaRESUMEN
INTRODUCTION: The purpose of this study was to evaluate the accuracy of Le Fort I surgery by comparing planned surgical movements with actual outcomes. MATERIALS AND METHODS: A minimum number of seven consecutive cases that had undergone a Le Fort I osteotomy procedure alone or in combination with a mandibular osteotomy from six different hospital units in the East of England between 2009 and 2010 were identified. A total of 56 cases met the inclusion criteria where surgical splints were used and model surgery had been performed. Pre- and post-operative lateral cephalograms were digitised using Dolphin© imaging software (Version 10.0) and three cephalometric points were assessed to measure precision of surgical movements: A point (A-pt); Upper incisor tip (U1 tip); and Upper first molar occlusal point (U6 occ). The final position of the maxilla was compared to the planned position. RESULTS: In 71% of cases surgical movements were within 2â mm and 20% of this group were within 1â mm of the predicted position. The mean accuracy was 1.39â mm (SD 0.92â mm) for the former and 0.78â mm (SD 0.58â mm) for the latter. Accuracy correlated negatively with increased surgical complexity, particularly posterior differential impactions of the maxilla. There was no statistically significant difference between centres. CONCLUSIONS: Pre-operative surgical planning of Le Fort I osteotomies was generally accurate. This study demonstrates that different operators across six centres produced consistent surgical outcomes and this confirms previously reported data.
Asunto(s)
Maxilar , Osteotomía Le Fort , Cefalometría , Estudios Retrospectivos , Resultado del TratamientoRESUMEN
Although extraocular muscles are commonly affected by myasthenia gravis (MG) at presentation, a treatment-resistant ophthalmoplegic complication of MG (OP-MG) occurs in younger patients with African-genetic ancestry. In MG, pathogenic antibodies activate complement-mediated muscle damage and this may be potentiated in some OP-MG cases because of relative deficiency of decay-accelerating factor/CD55. Extending this argument, we hypothesized that OP-MG individuals may harbor African-specific polymorphisms in key genes influencing extraocular muscle remodeling. We screened the regulatory region of the transforming growth factor beta-1 (TGFB1) gene encoding the cytokine pivotal in muscle healing responses. We show the frequency of an African-specific polymorphism TGFB1 c.-387 T (rs11466316) among South Africans with African-genetic ancestry is higher than 1000 Genomes African controls (17.2% vs 4.8%; P<1 × 10(-7)), and associates with juvenile OP-MG (28%; P=0.043). Further, TGFB1 -387 C>T is functional because it represses the TGFB1 promoter construct basal activity by fivefold, and OP-MG fibroblasts (-387 C/T or T/T) have lower basal TGFB1 mRNA transcripts compared with controls (-387 C/C)(P=0.001). Co-transfections with Sp1 show less responsiveness of the -387 T promoter compared with wild-type -387 C (P=0.015). Our findings suggest that population-specific alleles may lower TGFB1 expression, thereby influencing OP-MG susceptibility by inhibiting extraocular muscle CD55 upregulation and/or altered endplate remodeling.
Asunto(s)
Estudios de Asociación Genética , Miastenia Gravis/genética , Oftalmoplejía/genética , Factor de Crecimiento Transformador beta1/genética , Adolescente , Adulto , Población Negra , Antígenos CD55/genética , Femenino , Fibroblastos/metabolismo , Genotipo , Haplotipos , Humanos , Masculino , Miastenia Gravis/complicaciones , Miastenia Gravis/patología , Oftalmoplejía/etiología , Oftalmoplejía/patología , Polimorfismo de Nucleótido Simple , Regiones Promotoras Genéticas , ARN Mensajero/genéticaRESUMEN
A growing body of work has shown that the highly homologous T-box transcription factors TBX2 and TBX3 play critical but distinct roles in embryonic development and cancer progression. For example, TBX2 and TBX3 are up-regulated in several cancers and recent evidence suggests that whereas TBX2 functions as a pro-proliferative factor, TBX3 inhibits cell proliferation but promotes cancer cell migration and invasion. While the molecular mechanisms regulating these functions of TBX2 and TBX3 are poorly understood we recently reported that the TGF-ß1 signaling pathway up-regulates TBX3 expression to mediate, in part, its well described anti-proliferative and pro-migratory roles. The TBX3 targets responsible for these functions were however not identified. Here we reveal for the first time that the TGF-ß1 signaling pathway represses TBX2 transcriptionally and we provide a detailed mechanism to show that this is mediated by TBX3. Furthermore, we implicate the down-regulation of TBX2 in the anti-proliferative function of the TGF-ß1-TBX3 axis. These findings have important implications for our understanding of the regulation of TBX2 and TBX3 and shed light on the mechanisms involved in the anti-proliferative and pro-migratory roles of TGF-ß1.
Asunto(s)
Proliferación Celular/efectos de los fármacos , Proteínas de Dominio T Box/metabolismo , Factor de Crecimiento Transformador beta1/farmacología , Animales , Sitios de Unión/genética , Western Blotting , Línea Celular , Línea Celular Tumoral , Regulación hacia Abajo/efectos de los fármacos , Expresión Génica/efectos de los fármacos , Humanos , Mutación , Proteínas Oncogénicas/genética , Proteínas Oncogénicas/metabolismo , Regiones Promotoras Genéticas/genética , Unión Proteica/efectos de los fármacos , Interferencia de ARN , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Transducción de Señal/genética , Proteínas de Dominio T Box/genéticaRESUMEN
The evolutionarily conserved T-box family of transcription factors have critical and well-established roles in embryonic development. More recently, T-box factors have also gained increasing prominence in the field of cancer biology where a wide range of cancers exhibit deregulated expression of T-box factors that possess tumour suppressor and/or tumour promoter functions. Of these the best characterised is TBX2, whose expression is upregulated in cancers including breast, pancreatic, ovarian, liver, endometrial adenocarcinoma, glioblastomas, gastric, uterine cervical and melanoma. Understanding the role and regulation of TBX2, as well as other T-box factors, in contributing directly to tumour progression, and especially in suppression of senescence and control of invasiveness suggests that targeting TBX2 expression or function alone or in combination with currently available chemotherapeutic agents may represent a therapeutic strategy for cancer.
Asunto(s)
Neoplasias/patología , Proteínas de Dominio T Box/fisiología , Animales , Daño del ADN , Humanos , Transducción de SeñalRESUMEN
While it is well known that carotid artery dissection can cause hypoglossal palsy, which can cause muscle atrophy and fat tissue replacement in the chronic stage but what is less well known is the acute edematous stage, which can mimic tongue angioedema. We present a case report of a 52-year-old man presented to accident and emergency department with 3 hr history of right-side tongue swelling. He was initially diagnosed with angioedema and treated with corticosteroids and antihistamines. His tongue swelling persisted and subsequently developed unilateral weakness. Magnetic resonance imaging scan of the tongue, head, and neck revealed denervation of the right half of the tongue because of injury to hypoglossal nerve during extracranial internal carotid artery (ICA) dissection. There was no evidence of ischemic complication of right cerebral artery distribution. He was commenced on antiplatelet therapy to prevent cerebral ischemia as a prophylactic measure. Swelling and weakness of the tongue subsided in the following months. We believe that hypoglossal palsy caused by ICA dissection should be considered in the differential diagnosis of patients who present with acute tongue swelling.
Asunto(s)
Disección de la Arteria Carótida Interna/complicaciones , Edema/etiología , Traumatismos del Nervio Hipogloso/diagnóstico , Enfermedades de la Lengua/etiología , Humanos , Traumatismos del Nervio Hipogloso/etiología , Imagen por Resonancia Magnética , Masculino , Persona de Mediana EdadRESUMEN
An important function of all organisms is to ensure that their genetic material remains intact and unaltered through generations. This is an extremely challenging task since the cell's DNA is constantly under assault by endogenous and environmental agents. To protect against this, cells have evolved effective mechanisms to recognize DNA damage, signal its presence, and mediate its repair. While these responses are expected to be highly regulated because they are critical to avoid human diseases, very little is known about the regulation of the expression of genes involved in mediating their effects. The Nucleotide Excision Repair (NER) is the major DNA-repair process involved in the recognition and removal of UV-mediated DNA damage. Here we use a combination of in vitro and in vivo assays with an intermittent UV-irradiation protocol to investigate the regulation of key players in the DNA-damage recognition step of NER sub-pathways (TCR and GGR). We show an up-regulation in gene expression of CSA and HR23A, which are involved in TCR and GGR, respectively. Importantly, we show that this occurs through a p53 independent mechanism and that it is coordinated by the stress-responsive transcription factor USF-1. Furthermore, using a mouse model we show that the loss of USF-1 compromises DNA repair, which suggests that USF-1 plays an important role in maintaining genomic stability.
Asunto(s)
Daño del ADN/genética , Reparación del ADN/genética , ADN/genética , Factores Estimuladores hacia 5'/genética , Animales , Biopsia , Proteínas Portadoras/genética , Proteínas Portadoras/metabolismo , Supervivencia Celular/efectos de la radiación , ADN/efectos de la radiación , Enzimas Reparadoras del ADN/genética , Enzimas Reparadoras del ADN/metabolismo , Proteínas de Unión al ADN/genética , Proteínas de Unión al ADN/metabolismo , Regulación de la Expresión Génica/efectos de la radiación , Inestabilidad Genómica , Proteínas HSP70 de Choque Térmico/genética , Proteínas HSP70 de Choque Térmico/metabolismo , Humanos , Queratinocitos/citología , Queratinocitos/metabolismo , Queratinocitos/efectos de la radiación , Ratones , Ratones Noqueados , Proteínas Mitocondriales/genética , Proteínas Mitocondriales/metabolismo , ARN Interferente Pequeño , Rayos UltravioletaRESUMEN
The use of benzimidazole-based trinuclear ruthenium(II)-arene complexes (1-3) to selectively target the rare cancer rhabdomyosarcoma is reported. Preliminary cytotoxic evaluations of the ruthenium complexes in an eight-cancer cell line panel revealed enhanced, selective cytotoxicity toward rhabdomyosarcoma cells (RMS). The trinuclear complex 1 was noted to show superior short- and long-term cytotoxicity in RMS cell lines and enhanced selectivity relative to cisplatin. Remarkably, 1 inhibits the migration of metastatic RMS cells and maintains superior activity in a 3D multicellular spheroid model in comparison to that of the clinically used cisplatin. Mechanistic insights reveal that 1 effectively induces genomic DNA damage, initiates autophagy, and prompts the intrinsic and extrinsic apoptotic pathways in RMS cells. To the best of our knowledge, 1 is the first trinuclear ruthenium(II) arene complex to selectively kill RMS cells in 2D and 3D cell cultures.
Asunto(s)
Antineoplásicos , Apoptosis , Complejos de Coordinación , Rabdomiosarcoma , Rutenio , Humanos , Rabdomiosarcoma/tratamiento farmacológico , Rabdomiosarcoma/patología , Antineoplásicos/farmacología , Antineoplásicos/química , Antineoplásicos/síntesis química , Línea Celular Tumoral , Rutenio/química , Rutenio/farmacología , Complejos de Coordinación/farmacología , Complejos de Coordinación/química , Complejos de Coordinación/síntesis química , Apoptosis/efectos de los fármacos , Ensayos de Selección de Medicamentos Antitumorales , Relación Estructura-Actividad , Daño del ADN/efectos de los fármacos , Bencimidazoles/farmacología , Bencimidazoles/química , Bencimidazoles/síntesis química , Autofagia/efectos de los fármacos , Movimiento Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacosRESUMEN
Herein, we present a comprehensive review focusing on synthetic strategies, detailed structural analysis, and anticancer activity investigations of complexes following the general formula [LnM(µ-diphosphine)M'Lm] where M = group 8 metal; M' = any transition metal; µ-diphosphine = bridging ligand; Ln and Lm = ligand spheres). Both homo- and heteromultimetallic complexes will be discussed in detail. We review in vitro, in vivo and in silico anticancer activity investigations, in an attempt to draw comparisons between the various complexes and derive structure-activity relationships (SAR). This review solely focuses on complexes falling under the general formula stated above that have been studied for their anticancer activities, other complexes falling into that scheme but which have not undergone anticancer testing are not included in this review. We compare the anticancer activities of these complexes to their mononuclear counterparts, and a positive control (cisplatin) when possible and present a summary of all existing data to date and attempt to draw some conclusions on the future development of these complexes.
Asunto(s)
Antineoplásicos , Complejos de Coordinación , Fosfinas , Elementos de Transición , Antineoplásicos/farmacología , Antineoplásicos/química , Antineoplásicos/síntesis química , Humanos , Ligandos , Fosfinas/química , Fosfinas/farmacología , Complejos de Coordinación/química , Complejos de Coordinación/farmacología , Complejos de Coordinación/síntesis química , Elementos de Transición/química , Elementos de Transición/farmacología , Relación Estructura-Actividad , Ensayos de Selección de Medicamentos Antitumorales , Estructura Molecular , Animales , Proliferación Celular/efectos de los fármacosRESUMEN
Trinuclear ruthenium(II) polypyridyl complexes anchored to benzimidazole-triazine / trisamine scaffolds were investigated as photosensitizers for photodynamic therapy. The trinuclear complexes were noted to produce a significant amount of singlet oxygen in both DMF and aqueous media, are photostable and show appreciable emission quantum yields (ɸem). In our experimental setting, despite the moderate phototoxic activity in the HeLa cervical cancer cell line, the phototoxic indices (PI) of the trinuclear complexes are superior relative to the PIs of a clinically approved photosensitizer, Photofrin®, and the pro-drug 5-aminolevulinic acid (PI: >7 relative to PI: >1 and PI: 4.4 for 5-aminolevulinic acid and Photofrin®, respectively). Furthermore, the ruthenium complexes were noted to show appreciable long-term cytotoxicity upon light irradiation in HeLa cells in a concentration-dependent manner. Consequently, this long-term activity of the ruthenium(II) polypyridyl complexes embodies their ability to reduce the probability of the recurrence of cervical cancer. Taken together, this presents a strong motivation for the development of polymetallic complexes as anticancer agents.
Asunto(s)
Complejos de Coordinación , Fotoquimioterapia , Fármacos Fotosensibilizantes , Rutenio , Neoplasias del Cuello Uterino , Humanos , Fármacos Fotosensibilizantes/farmacología , Fármacos Fotosensibilizantes/química , Fármacos Fotosensibilizantes/síntesis química , Células HeLa , Neoplasias del Cuello Uterino/tratamiento farmacológico , Neoplasias del Cuello Uterino/patología , Rutenio/química , Femenino , Complejos de Coordinación/farmacología , Complejos de Coordinación/química , Complejos de Coordinación/síntesis química , Fotoquimioterapia/métodos , Antineoplásicos/farmacología , Antineoplásicos/química , Antineoplásicos/síntesis química , Piridinas/química , Piridinas/farmacología , Oxígeno Singlete/metabolismoRESUMEN
In an effort to develop new potent anticancer agents, two Schiff base rhenium(I) tricarbonyl complexes, containing the ubiquitous aminoquinoline scaffold, were synthesized. Both aminoquinoline ligands and Re(I) complexes showed adequate stability over a 48-h incubation period. Furthermore, the cytotoxic activity of the precursor ligands and rhenium(I) complexes were evaluated against the hormone-dependent MCF-7 and hormone-independent triple negative MDA-MB-231 breast cancer cell lines. Inclusion of the [Re(CO)3Cl]+ entity significantly enhanced the cytotoxicity of the aminoquinoline Schiff base ligands against the tested cancer cell lines. Remarkably, the incorporation of the Schiff-base iminoquinolyl entity notably enhanced the cytotoxic activity of the Re(I) complexes, in comparison with the iminopyridyl entity. Notably, the quinolyl-substituted complex showed up to three-fold higher activity than cisplatin against breast cancer cell lines, underpinning the significance of the quinoline pharmacophore in rational drug design. In addition, the most active Re(I) complex showed better selectivity towards the breast cancer cells over non-tumorigenic FG-0 cells. Western blotting revealed that the complexes increased levels of γH2AX, a key DNA damage response protein. Moreover, apoptosis was confirmed in both cell lines due to the detection of cleaved PARP. The complexes show favourable binding affinities towards both calf thymus DNA (CT-DNA), and bovine serum albumin (BSA), and the order of their interactions align with their cytotoxic effects. The in silico molecular simulations of the complexes were also performed with CT-DNA and BSA targets.