This paper describes the antitumoral activity of branched-chain fatty acid (BCFA) in human breast cancer cells with an emphasis on its effect on fatty acid biosynthe sis. First, the relationship between chain-length and antitumoral activity was studied. The highest activity was observed with iso-16:0, and the activity decreased with increase or decrease of the chain-lengths from C 16:0. Anteiso-BCFA, as well as iso-series, was cytotoxic to the breast cancer cells. Cytotoxicity of BCFA was comparable to that of conjugated linoleic acid known as antitumoral fatty acid. Incubation of breast cancer cells with BCFA (13-methyltetradecanoic acid) significantly reduced the [14C] acetate incorporation into free fatty acid and fatty acid esters, showing the inhibition of fatty acid biosynthesis by BCFA. Examination of substrate level effect found that BCFA slightly inhibited fatty acid synthetase and acetyl-CoA carboxylase, and significantly the glucose-6-phosphate dehydrogenase which was the main NADPH generating system in breast cancer cells. The present study thus suggests that BCFA synthetically lowers the fatty acid biosynthesis by reducing the pre cursors, in addition to its direct inhibitory effect on fatty acid synthetase.

Adult T-cell leukemia (ATL) is a fatal malignancy of T lymphocytes caused by human T-cell leukemia virus type 1 (HTLV-1) infection and remains incurable. Carotenoids are a family of natural pigments and have several biological functions. Among carotenoids, fucoxanthin is known to have antitumorigenic activity, but the precise mechanism of action is not elucidated. We evaluated the anti-ATL effects of fucoxanthin and its metabolite, fucoxanthinol. Both carotenoids inhibited cell viability of HTLV-1-infected T-cell lines and ATL cells, and fucoxanthinol was approximately twice more potent than fucoxanthin. In contrast, other carotenoids, b-carotene and astaxanthin, had mild inhibitory effects on HTLV-1-infected T-cell lines. Importantly, uninfected cell lines and normal peripheral blood mononuclear cells were resistant to fucoxanthin and fucoxanthinol. Both carotenoids induced cell cycle arrest during G 1 phase by reducing the expression of cyclin D1, cyclin D2, CDK4 and CDK6, and inducing the expression of GADD45a, and induced apoptosis by reducing the expression of Bcl-2, XIAP, cIAP2 and survivin. The induced apoptosis was associated with activation of caspase-3, -8 and -9. Fucoxanthin and fucoxanthinol also suppressed IjBa phosphorylation and JunD expression, resulting in inactivation of nuclear factor-jB and activator protein-1. Mice with severe combined immunodeficiency harboring tumors induced by inoculation of HTLV-1-infected T cells responded to treatment with fucoxanthinol with suppression of tumor growth, showed extensive tissue distribution of fucoxanthinol, and the presence of therapeutically effective serum concentrations of fucoxanthinol. Our preclinical data suggest that fucoxanthin and fucoxanthinol could be potentially useful therapeutic agents for patients with ATL. ' 2008 Wiley-Liss, Inc.Key words: fucoxanthin; fucoxanthinol; ATL; NF-jB; AP-1 Adult T-cell leukemia (ATL) is a unique malignancy of mature CD4 1 T cells caused by human T-cell leukemia virus type 1 (HTLV-1). 1-3 Clinically, ATL is subclassified into 4 subtypes: acute, lymphoma, chronic and smoldering. In the relatively indolent smoldering and chronic types, the median survival time is 2 years. However, at present, there is no accepted curative therapy for ATL and the condition often progresses to death with a median survival time of 13 months in aggressive ATL. 4 Death is usually due to severe infection or hypercalcemia, often associated with resistance to intensive, combined chemotherapy. Therefore, the establishment of new therapeutic strategies for ATL is very important.Carotenoids are a family of natural pigments with at least 600 members. They have several biological functions, including provitamin A activity, radical scavenging, singlet oxygen-quenching activity, immunomodulation and chemopreventive effects on carcinogenesis. 5 Among the carotenoids, b-carotene and lycopene, which are found in terrestrial plants such as vegetables and fruits, have been extensively studied with regard to physiological functions. 5 Marine organis...

This study thus proves the effectiveness of benzo[c]phenanthridine derivatives as anti-cancer agent in vivo for the first time, and discusses the mechanisms responsible for the selective cytotoxicity.

Ultrastructural and morphometrical studies were conducted on vascular tissue from 205 human Japanese specimens ranging in age from 15 weeks’ gestation to 90 years. Comparison of aorta size with overall body length by allometry revealed that the aging aorta has growth and involution stages comparable to other organs, and that progressive increase in aortic diameter was the major involutional change. The cellular and extracellular components of the medial sections of thoracic and abdominal aorta, renal artery, and superior mesenteric artery were quantitated from electron micrographs and compared at different ages. It was found that the renal artery rapidly accumulated extracellular material with increasing age; in the aortic tissue, however, the peak occurrence of extracellular material occurred at pubescence. Ultrastructural studies revealed a general tendency of aging medial smooth muscle cells to transform from a smooth, rounded morphology to become irregularly shaped.

To identify a gene responsible for multiple endocrine neoplasia type 1 (MEN1), we attempted to isolate potentially transcribable fragments from cosmid clones derived from a region on chromosome 11q13 where genetic linkage studies and analyses of loss of heterozygosity in MEN1-associated tumors have localized the MEN1 gene. By an exon-amplification method, we recovered three exon-like sequences from one of these clones, cCI11-367, and using these sequences as probes we were able to isolate new clones from cerebrum, cerebellum, and fetal-liver cDNA libraries. Sequence analysis of these cDNA clones revealed that the transcribed gene, designated ZFM1, encodes a novel 623-amino-acid protein containing domains with interesting structural properties including a nuclear transport domain, a metal binding motif, and glutamine- and proline-rich regions. Analysis by the reverse-transcriptase polymerase chain reaction (RT-PCR) indicated that this gene is expressed in various tissues including endocrine organs such as thyroid gland, pancreas, adrenal gland, and ovary. These data suggest that ZFM1 might be a candidate for mutations that cause MEN1.