A new series of acetohydroxamates shows in vitro and in vivo anticancer activity against melanoma.

Cancer treatment is challenging, mainly due to high levels of drug toxicity and the resistance of tumours to chemotherapy. Hydroxamic acid derivatives have recently aroused attention due to their potential to treat malignancies. In the present study, we sought to investigate the anticancer effects of a new series of synthetic acetohydroxamates. The in vitro cytotoxic and antiproliferative effects of 11 synthetic acetohydroxamates were evaluated against the melanoma cell line A375. Apoptosis, cell cycle, and autophagy assays were employed to elucidate the cell death pathways induced by the compounds. The in vivo pharmacokinetic profiles of the most promising compounds were determined in CD-1 mice, while the in vivo antitumour efficacies were evaluated using the A375 melanoma xenograft model in nude mice. MTT assays revealed that all compounds presented concentration-dependent cytotoxicity against the A375 cell line. AKS 61 produced the most favourable antiproliferative activity according to the sulphorhodamine B and clonogenic assays. AKS 61 treatment resulted in decreased mitochondrial membrane potential and increased apoptosis and autophagy in the A375 cell line. However, AKS 61 failed to prevent in vivo tumour growth in a melanoma xenograft, whereas compound AKS 7 was able to inhibit tumour growth when administered orally. These in vivo findings may be explained by a more favourable pharmacokinetic profile presented by AKS 7 when compared to AKS 61. Taken together, these results suggest that acetohydroxamates have potential anticancer effects and will guide future optimisation of these molecules to allow for further non-clinical development.

Intranigral LPS administration produces dopamine, glutathione but not behavioral impairment in comparison to MPTP and 6-OHDA neurotoxin models of Parkinson's disease.

The current investigation compared intranigral lipopolysaccharide (LPS), 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and 6-hydroxydopamine (6-OHDA) administrations, in the light of neurochemical, behavioral and endogenous antioxidant glutathione alterations. All the results were collected 1, 3 and 7 days after the lesions. LPS produced a delayed reduction of striatal dopamine, whereas homovanillic acid was drastically increased at the first time-point. Comparatively, MPTP promoted dopamine reduction 3 and 7 days with increase of homovanillic acid. Whilst, 6-OHDA generated initial increase of dopamine and homovanillic acid followed by subsequent decrease of this neurotransmitter accompanied by reductions of dopamine metabolites at the same periods. Furthermore, nigral glutathione demonstrated to be a far more sensitive target for LPS than for MPTP or 6-OHDA. Behavioral data indicated impairments induced by MPTP, 6-OHDA but not LPS. In conclusion, it is suggested that intranigral LPS can provide new insights about neuroinflammation, simulating features of the pre-motor phase of Parkinson's disease.

Hyperpigmentant activity of leaves and flowers extracts of Pyrostegia venusta on murine B16F10 melanoma.

ETHNOPHARMACOLOGICAL RELEVANCE: Pyrostegia venusta is a native Brazilian plant which has a variety of uses in traditional folk medicine including the treatment of vitiligo. However, its effectiveness on melanogenesis is not yet elucidated. AIM OF THE STUDY: This study aimed to investigate the melanogenic activity of hydroalcoholic extracts from the leaves and flowers of P. venusta on murine B16F10 melanoma cells. MATERIALS AND METHODS: Different concentrations of the hydroalcoholic extracts of flowers and leaves of P. venusta were evaluated in trials of spontaneous melanin content (4 days), and cell viability by the MTT assay in murine B16F10 cells, and in the mushroom tyrosinase activity in vitro. RESULTS: Both extracts, leaves (0.1; 0.3; 1 and 3 µg/mL) and flowers (0.03 and 0.1 µg/mL) increased the melanin content in a concentration dependent manner after 4 days of incubation on melanoma cells. Leaves extract promoted enhancement of melanogenesis with maximum effect of 33.3±3% (3 µg/mL), and the flower extract increased in 23.4±3% (0.1 µg/mL). The cell viability test using MTT showed that in the same tested concentrations of both extracts no cell death was detected. Actually, either extract was not able to cause any change in the tyrosinase activity. HPLC analysis of P. venusta extracts found 0.09% and 1.08% of allantoin on leaves and flowers extracts, respectively. CONCLUSIONS: The leaves and flowers extracts of P. venusta stimulates B16F10 melanogenesis at very low concentrations. These findings support the folk medicinal use of P. venusta on the treatment of hypopigmentation diseases, such as vitiligo.

Behavioral, neurochemical and histological alterations promoted by bilateral intranigral rotenone administration: a new approach for an old neurotoxin.

Rotenone exposure in rodents provides an interesting model for studying mechanisms of toxin-induced dopaminergic neuronal injury. However, several aspects remain unclear regarding the effects and the accuracy of rotenone as an animal model of Parkinson's disease (PD). In order to counteract these limitations, this study characterized a precise neurotoxin-delivery strategy employing the bilateral intranigral administration protocol of rotenone as a reliable model of PD. We performed bilateral intranigral injections of rotenone (12 µg) and subsequent general activity (1, 10, 20, and 30 days after rotenone) and cognitive (7, 8, 15, and 30 days after rotenone) evaluations followed by neurochemical and immunohistochemical tests. We have observed that rotenone was able to produce a remarkable reduction on the percentage of tyrosine hydroxylase immunoreactive neurons (about 60%) within the substantia nigra pars compacta. Dopamine (DA) was severely depleted at 30 days after rotenone administration, similarly to its metabolites. In addition, an increase in DA turnover was detected at the same time-point. In parallel, striatal serotonin and its metabolite were found to be increased 30 days after the neurotoxic insult, without apparent modification in the serotonin turnover. Besides, motor behavior was impaired, mainly 1 day after rotenone. Furthermore, learning and memory processes were severely disrupted in different time-points, particularly at the training and test session (30 days). We now provide further evidence of a time-dependent neurodegeneration associated to cognitive impairment after the single bilateral intranigral administration of rotenone. Thus, it is proposed that the current rotenone protocol provides an improvement regarding the existing rotenone models of PD.