The relevance of BRAF G469A mutation in determining the response to therapy in metastatic melanoma

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Aurora kinase B inhibition reduces the proliferation of metastatic melanoma cells and enhances the response to chemotherapy

Background: The poor response to chemotherapy and the brief response to vemurafenib in metastatic melanoma patients, make the identification of new therapeutic approaches an urgent need. Interestingly the increased expression and activity of the Aurora kinase B during melanoma progression suggests it as a promising therapeutic target. Methods: The efficacy of the Aurora B kinase inhibitor barasertib-HQPA was evaluated in BRAF mutated cells, sensitive and made resistant to vemurafenib after chronic exposure to the drug, and in BRAF wild type cells. The drug effectiveness has been evaluated as cell growth inhibition, cell cycle progression and cell migration. In addition, cellular effectors of drug resistance and response were investigated. Results: The characterization of the effectors responsible for the resistance to vemurafenib evidenced the increased expression of MITF or the activation of Erk1/2 and p-38 kinases in the newly established cell lines with a phenotype resistant to vemurafenib. The sensitivity of cells to barasertib-HQPA was irrespective of BRAF mutational status. Barasertib-HQPA induced the mitotic catastrophe, ultimately causing apoptosis and necrosis of cells, inhibited cell migration and strongly affected the glycolytic metabolism of cells inducing the release of lactate. In association i) with vemurafenib the gain in effectiveness was found only in BRAF(V600K) cells while ii) with nab-paclitaxel, the combination was more effective than each drug alone in all cells. Conclusions: These findings suggest barasertib as a new therapeutic agent and as enhancer of chemotherapy in metastatic melanoma treatment

A model radiopharmaceutical agent targeted to translocator protein 18 kDa (TSPO)

A stable Re complex containing an imidazopyridine ligand with a high affinity for TSPO has been synthesized as a model for new 99mTc or 188/186Re-based radiopharmaceuticals to be used in SPECT diagnosis or in therapy, respectively. The new complex fac- [ReBr(CO)3(TZ6)], structurally characterized, showed high affinity (nanomolar concentration) for the target protein

A new complex of curcumin with sulfobutylether-β-cyclodextrin: characterization studies and in vitro evaluation of cytotoxic and antioxidant activity on HepG-2 cells

Curcumin is a natural polyphenol with anti-oxidative, anti-inflammatory and anti-cancer properties but its therapeutic potential is substantially hindered by the rather low water solubility and bioavailability. Thus, in this work, a new soluble inclusion complex of curcumin with sulfobutylether--cyclodextrin (SBE-β-CD) was prepared in solution and at the solid state using different preparation techniques and characterized by FT-IR, NMR, DSC, SEM, phase solubility studies and Job’s plot method. Results clearly indicate that curcumin reacts with SBE-β-CD to form a host-guest complex with an apparent formation constant of 1455 M-1. Moreover, SBE-β-CD strongly increases water solubility of curcumin (from 0.56 to 102.78 g/ml, at 25◦C) and lyophilization method seems to be the best preparation technique to obtain the complex at the solid state. Finally, an in vitro test on a human hepatic cancer cell line (HepG-2) shows that complexation positively influences curcumin anticancer and antioxidant activit

Thermoresponsive mucoadhesive hydrogel based on Pluronic F127/ thiolated glycol chitosan for intravesical administration of celecoxib/ gemcitabine

In recent years, mucoadhesivein situ gelling formulations for intravesical application have been studied to improve the therapeutic outcomes of bladder cancer patients. Here, we carefully tuned a Pluronic F127-based thermoresponsive gel using two mucoadhesive thiolated derivatives of glycol chitosan, S-preactivated N-acetylcysteine (NAC)- and glutathione (GSH)-glycol chitosan (GC). The gel was loaded with a combination of Gemcitabine (GEM) and Celecoxib (CEX), and the aqueous solubility of the latter was increased for a synergic influence between Pluronic and the inclusion complex of 2-Hydroxypropyl-& beta;-cyclodextrin/CEX. The effect of the inclusion complex of two mucoadhesive polymers on rheological features of Pluronic based gels was highlighted to select the best performance. Finally, ex-vivo retention studies, mucosal penetration and in-vitro drug release of the selected systems were monitored for 24 h, providing enhanced retention properties (50% after 6 h) and continued drug release