5 research outputs found
Subcellular duplex DNA and Gâquadruplex interaction profiling of a hexagonal PtII metallacycle
[Abstract] Metalâdriven selfâassembly afforded a multitude of fascinating supramolecular coordination complexes (SCCs) with applications as catalysts, hostâguest, and stimuliâresponsive systems. However, the interest in the biological applications of SCCs is only starting to emerge and thorough characterization of their behavior in biological milieus is still lacking. Herein, we report on the synthesis and detailed inâcell tracking of a Pt2L2 metallacycle. We show that our hexagonal supramolecule accumulates in cancer cell nuclei, exerting a distinctive blue fluorescence staining of chromatin resistant to UV photobleaching selectively in nucleolar G4ârich regions. SCC coâlocalizes with epitopes of the quadruplexâspecific antibody BG4 and replaces other wellâknown G4 stabilizers. Moreover, the photophysical changes accompanying the metallacycle binding to G4s in solution (fluorescence quenching, absorption enhancement) also take place intracellularly, allowing its subcellular interaction tracking.Ministerio de EconomĂa, Industria y Competitividad; CTQ2016-75629-
Computed determination of the in vitro optimal chemocombinations of sphaeropsidin A with chemotherapeutic agents to combat melanomas
PURPOSE: Evasion to new treatments of advanced melanoma is still associated with a poor prognosis. Choosing the best combination of agents that can bypass resistance mechanisms remains a challenge. Sphaeropsidin A (Sph A) is a fungal bioactive secondary metabolite previously shown to force melanoma cells to undergo apoptosis via cell volume dysregulation. This work studied its in vitro combination with cytotoxic chemotherapeutics in a rational manner. METHODS: Four melanoma cell lines harboring different sensitivity levels to pro-apoptotic stimuli were used to build a predictive response surface model allowing the determination of the optimal in vitro combinations of Sph A with two drugs, i.e., cisplatin or temozolomide, owing to a limited set of experimentations. RESULTS: Testing 12 experimental combinations allowed us to build an accurate predictive model that considers the complexity of the drug interaction and determines the optimal combinations according to the endpoint chosen, i.e., the maximal cytotoxic effects. Therefore, combining 4 ”M Sph A with 75 ”M cisplatin concomitantly for 72 h improved its cytotoxic effects on melanoma cells in a synergistic manner. An optimal in vitro treatment schedule was also obtained for temozolomide. CONCLUSIONS: The use of a response surface model offers the possibility of reducing the experiments while determining accurately the optimal combinations. We herein highlighted that combining the Na+/K+/2Cl- cotransporter and/or anion exchanger inhibitor Sph A with chemotherapeutic agents could improve the therapeutic benefits of conventional chemotherapies against advanced melanomas, particularly because Sph A exerts cytotoxic effects regardless of the genetic BRAF and NRAS status.status: publishe
Computed determination of the in vitro optimal chemocombinations of sphaeropsidin A with chemotherapeutic agents to combat melanomas
Purpose: Evasion to new treatments of advanced melanoma is still associated with a poor prognosis. Choosing the best combination of agents that can bypass resistance mechanisms remains a challenge. Sphaeropsidin A (Sph A) is a fungal bioactive secondary metabolite previously shown to force melanoma cells to undergo apoptosis via cell volume dysregulation. This work studied its in vitro combination with cytotoxic chemotherapeutics in a rational manner. Methods: Four melanoma cell lines harboring different sensitivity levels to pro-apoptotic stimuli were used to build a predictive response surface model allowing the determination of the optimal in vitro combinations of Sph A with two drugs, i.e. cisplatin or temozolomide, owing to a limited set of experimentations. Results: Testing 12 experimental combinations allowed us to build an accurate predictive model that considers the complexity of the drug interaction and determines the optimal combinations according to the endpoint chosen, i.e. the maximal cytotoxic effects. Therefore, combining 4 ”M Sph A with 75 ”M cisplatin concomitantly for 72 h improved its cytotoxic effects on melanoma cells in a synergistic manner. An optimal in vitro treatment schedule was also obtained for temozolomide. Conclusions: The use of a response surface model offers the possibility of reducing the experiments while determining accurately the optimal combinations. We herein highlighted that combining the Na+/K+/2Clâ cotransporter and/or anion exchanger inhibitor Sph A with chemotherapeutic agents could improve the therapeutic benefits of conventional chemotherapies against advanced melanomas, particularly because Sph A exerts cytotoxic effects regardless of the genetic BRAF and NRAS status.SCOPUS: ar.jinfo:eu-repo/semantics/publishe
Extent of peritumoral brain edema correlates with prognosis, tumoral growth pattern, HIF1a expression and angiogenic activity in patients with single brain metastases
To analyze the prognostic value of the extent of peritumoral brain edema in patients operated for single brain metastases (BM), we retrospectively evaluated pre-operative magnetic resonance images in a discovery cohort of 129 patients and a validation cohort of 118 patients, who underwent neurosurgical resection of a single BM in two different hospitals. We recorded clinical parameters and immunohistochemically assessed the Ki67 index, the microvascularization patterns and the expression of hypoxia-induced factor 1 alpha (HIF1a) in the BM tissue specimens retrieved at neurosurgery. Statistical analysis including uni- and multivariate survival analyses were performed. Baseline characteristics were well balanced between the discovery and validation cohorts. In univariate analysis, we found a significant association of favorable overall survival time with young patient age, high Karnofsky performance score, low graded prognostic assessment (GPA) class, absence of extracranial metastases, adjuvant treatment with whole brain radiotherapy and, surprisingly, large brain edema. In multivariate analysis, only GPA and extent of brain edema remained independent prognostic parameters. The prognostic impact of the extent of brain edema was consistent in the two patient cohorts. Furthermore, we found a significant correlation of small brain edema with brain-invasive tumor growth pattern as assessed intraoperatively by the neurosurgeon, low neo-angiogenic activity and low expression of HIF1a. Extent of brain edema independently correlates with prognosis in patients operated for single BM. In conclusion, patients with small peritumoral edema have shorter survival times and their tumors are characterized by a more brain-invasive growth, lower HIF1a expression and less angiogenic activity