Proteasome inhibition and ROS generation by 4-nerolidylcatechol induces melanoma cell death.

Induction of apoptotic cell death in response to chemotherapy and other external stimuli has proved extremely difficult in melanoma, leading to tumor progression, metastasis formation and resistance to therapy. A promising approach for cancer chemotherapy is the inhibition of proteasomal activity, as the half-life of the majority of cellular proteins is under proteasomal control and inhibitors have been shown to induce cell death programs in a wide variety of tumor cell types. 4-Nerolidylcatechol (4-NC) is a potent antioxidant whose cytotoxic potential has already been demonstrated in melanoma tumor cell lines. Furthermore, 4-NC was able to induce the accumulation of ubiquitinated proteins, including classic targets of this process such as Mcl-1. As shown for other proteasomal inhibitors in melanoma, the cytotoxic action of 4-NC is time-dependent upon the pro-apoptotic protein Noxa, which is able to bind and neutralize Mcl-1. We demonstrate the role of 4-NC as a potent inducer of ROS and p53. The use of an artificial skin model containing melanoma also provided evidence that 4-NC prevented melanoma proliferation in a 3D model that more closely resembles normal human skin.

Ascorbic acid concentration is reduced in the secondary aqueous humour of glaucomatous patients.

BACKGROUND: We aimed to evaluate the ascorbic acid concentration in secondary aqueous humour (AH) from glaucomatous patients and to compare it with primary AH from primary open-angle glaucoma patients and non-glaucomatous patients. METHODS: Primary AH samples were prospectively obtained from clinically uncontrolled primary open-angle glaucoma patients and senile cataract patients (controls) prior to trabeculectomy and cataract surgery. Secondary AH samples were obtained from eyes with previous intraocular surgery, prior to trabeculectomy or cataract surgery. AH (0.1 mL) was aspirated by inserting a 26-gauge needle into the anterior chamber just before surgery and then immediately stored at -80 degrees C. The ascorbic acid concentration was determined in a masked fashion by high-pressure liquid chromatography. RESULTS: A total of 18 patients with senile cataract, 16 glaucomatous patients with primary AH (no previous intraocular surgery) and 11 glaucomatous patients with secondary AH (previous intraocular surgery) were included. There was no difference in mean age between groups (P = 0.15). The mean +/- standard deviation concentration of ascorbic acid in the secondary AH from glaucomatous patients (504 +/- 213 micromol/L [95% confidence interval {CI}, 383-624]) was significantly lower than the concentration of ascorbic acid found in the primary aqueous of primary open-angle glaucoma (919 +/- 427 micromol/L [95% CI, 709-1128]) and control patients (1049 +/- 433 micromol/L [95% CI, 848-1249]; P < 0.01, Kruskal-Wallis test). CONCLUSIONS: The ascorbic acid concentration in secondary AH of glaucomatous patients was approximately twofold lower in comparison with primary AH of glaucomatous and cataract patients. The implications of a reduced concentration of ascorbic acid in the secondary AH deserve further investigation.

Pharmacological activity of South American plants: effects on spontaneous in vivo lipid peroxidation.

The in vivo protective effects of methanol extracts of eight South American medicinal plants traditionally used as antiinflammatory were determined by means of spontaneous lipid peroxidation of liver tissue in rats. The production of TBARS was reduced in a dose dependent manner for A. macrocarpa (IC50 = 132 mg/kg), A. urundeuva (IC50 = 176 mg/kg), C. reticulata (IC50 = 561mg/kg) and S. obtusifolium (IC50 = 918 mg/kg). The extracts of P. peltata and U. tomentosa were only effective at a high concentration (300 mg/kg), although these values were not significant. The lyophilized latex of C. lechleri decreased the production of TBARS at a 200 mg/kg dose, although pro-oxidant effects were observed at lower doses (50 mg/kg). The extract of H. pallida was pro-oxidant at lower concentrations (50 mg/kg).