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Abstract: Histone deacetylase inhibitors (HDACi) have been discovered as potential drugs for cancer treatment. The effect of BL1521, a novel HDACi, on the cell cycle distribution and the induction of apoptosis was investigated in a panel of MYCN single copy and MYCN amplified neuroblastoma cell lines. BL1521 arrested neuroblastoma cells in the G1 phase and induced up to 30% apoptosis. Downregulation of CDK4, upregulation of p21WAF1/CIP1 and an increase of hypophosphorylated retinoblastoma protein were observed, indicating a possible mechanism for the cell-cycle arrest. BL1521 also induced downregulation of p27, which may underlie the observed induction of apoptosis. [Copyright &y& Elsevier]

In this paper, it is demonstrated that all-trans, 9-cis and 13-cis retinoic acid (RA) decreased the sensitivity of SK-N-BE(2)c neuroblastoma cells towards the chemotherapeutic agent cyclopentenyl cytosine (CPEC), a potent inhibitor of cytosine-5′-triphosphate synthetase. Retinoic acid attenuated CPEC-induced apoptosis as reflected by a decreased caspase-3 induction. Retinoic acid decreased the accumulation of CPEC, whereas the salvage of cytidine was strongly increased. Metabolic labeling studies using [3H]uridine showed a strongly decreased biosynthesis of CTP via CTP synthetase. Retinoic acid likely confers resistance of neuroblastoma cells to CPEC in part by slowing down proliferation, and in part by shifting the synthesis of CTP towards the salvage of cytidine, thereby bypassing CTP synthetase. [Copyright &y& Elsevier]

The N-terminal amino acid sequences and the electrophoretic mobilities of the subunits VIIa, VIIb and VIIc of cytochrome c oxidase purified from human heart were investigated and compared with those from human skeletal muscle and from bovine heart. In purified human heart cytochrome c oxidase, both so-called 'heart-type' and 'liver-type' isoforms of subunit VIIa were found. The first 30 residues of the N-terminal amino acid sequences of these 'heart-type' and 'liver-type' subunits VIIa showed nine differences. The two isoforms of subunit VIIa in human heart were present in almost equal amounts, in contrast to the situation in skeletal muscle, where the 'heart-type' subunit VIIa was predominant. Therefore, our results imply that in human heart a cytochrome c oxidase isoform pattern is present that differs from that found in skeletal muscle. Subunits VIIb and Vile purified from human heart oxidase proved to be very similar to their bovine heart counterparts. Our direct demonstration of the presence of subunit VIIb, the sequence of which has only recently been identified in the bovine heart enzyme, suggests that human cytochrome c oxidase also contains 13 subunits. We found no evidence for the presence of different isoforms of subunit VIIc in cytochrome c oxidase from human heart and skeletal muscle. We observed clear differences in the electrophoretic mobility of the subunits VIIa,b,c between bovine and human cytochrome c oxidase. On Tricine/glycerol/SDS/polyacrylamide gels the 'hearttype' and 'liver-type' subunits VIIa present in human heart cytochrome c oxidase migrated with almost the same electrophoretic mobility. Subunit VIIb migrated only slightly faster than subunit VIIa, whereas Vile proved to have the highest electrophoretic mobility on Tricine/SDS/glycerol/ polyacrylamide gels. Our findings may have implications for the elucidation of certain tissue-specific cytochrome c oxidase deficiencies in man. [ABSTRACT FROM AUTHOR]