Chemosensitization of glioblastoma cells by the histone deacetylase inhibitor MS275.

Glioblastoma is the most common primary brain tumor with a dismal prognosis, highlighting the need for novel treatment strategies. Here, we provide the first evidence that the histone deacetylase inhibitor, MS275, sensitizes glioblastoma cells for chemotherapy-induced apoptosis. Pretreatment of glioblastoma cells with MS275 causes acetylation of histone H3 protein and significantly enhances doxorubicin-induced apoptosis. Calculation of combination index showed that MS275 and doxorubicin acted in a synergistic manner to trigger apoptosis. Furthermore, pre-exposure to MS275 significantly increases apoptosis in response to temozolomide, etoposide, and cisplatin. In contrast, treatment with MS275 before the addition of vincristine and taxol significantly reduces the induction of apoptosis. Analysis of cell cycle alterations showed that treatment with MS275 triggers G1 cell cycle arrest, which in turn renders cells less sensitive to the cytotoxic effects of mitotic inhibitors, such as vincristine and taxol. Thus, these findings show for the first time that the histone deacetylase inhibitor, MS275, represents a promising strategy to prime glioblastoma cells for chemotherapy-induced apoptosis in a drug-specific manner.

NinaB combines carotenoid oxygenase and retinoid isomerase activity in a single polypeptide.

In animals, successful production of the visual chromophore (11-cis-retinal or derivatives thereof such as 11-cis-3-hydroxy-retinal) is essential for photoreceptor cell function and survival. These carotenoid-derived compounds must combine with a protein moiety (the opsin) to establish functional visual pigments. Evidence from cell culture systems has implicated that the retinal pigment epithelium protein of 65 kDa (RPE65) is the long-sought all-trans to 11-cis retinoid isomerase. RPE65 is structurally related to nonheme iron oxygenases that catalyze the conversion of carotenoids into retinoids. In vertebrate genomes, two carotenoid oxygenases and RPE65 are encoded, whereas in insect genomes only a single representative of this protein family, named NinaB (denoting neither inactivation nor afterpotential mutant B), is encoded. We here cloned and functionally characterized the ninaB gene from the great wax moth Galleria mellonella. We show that the recombinant purified enzyme combines isomerase and oxygenase (isomerooxygenase) activity in a single polypeptide. From kinetics and isomeric composition of cleavage products of asymmetrical carotenoid substrates, we propose a model for the spatial arrangement between substrate and enzyme. In Drosophila, we show that carotenoid-isomerooxygenase activity of NinaB is more generally found in insects, and we provide physiological evidence that carotenoids such as 11-cis-retinal can promote visual pigment biogenesis in the dark. Our study demonstrates that trans/cis isomerase activity can be intrinsic to this class of proteins and establishes these enzymes as key components for both invertebrate and vertebrate vision.