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Edward D Harris

Publications and source records attributed to Edward D Harris.

At least 19 recordsLinked to original sources
PubMed2006

Antiproliferative effects of citrus limonoids against human neuroblastoma and colonic adenocarcinoma cells.

Limonoids, a family of triterpenoids with putative anticancer properties, occur in fruits as glucosides and aglycones. Both highly purified forms were isolated from seeds and molasses of citrus fruits and tested for toxic effects against two human cancer cell lines, SH-SY5Y neuroblastoma and Caco-2 colonic adenocarcinoma, and a noncancerous mammalian epithelial Chinese hamster ovary (CHO) cells. Viability, as quantified by 3-[4,5-dimethylthiazol- 2-yl]-2,5-diphenyltetrazolium reduction and light microscopy, was shortened significantly (P < 0.001) in cancer cells exposed to aglycones, viz., limonin, nomilin, obacunone, and deacetylnomilin. SH-SY5Y cells were more sensitive than Caco-2 cells to the limonoids, whereas noncancerous CHO cells showed hardly any change in cell numbers or cell morphology. Aglycone toxicity was dose dependent, but below the killing potential of glucosides. This observation correlated with a slower rate of induction of caspase 3/7 activity by aglycones. A flow cytometric analysis of SH-SY5Y cells treated with glucosides and aglycones showed an increased ploidy, which is consistent with enhancing chromosomal abnormalities. The results confirm that limonoids exert a strong multifaceted lethal action against cancer cells, but are relatively ineffective against CHO cells. Of the two, metabolites derived from glucosides are the more likely progenitors of an apoptosis response in situ.

Animals↗
PubMed2005

Citrus limonoids induce apoptosis in human neuroblastoma cells and have radical scavenging activity.

Citrus limonoid glucosides, a family of fruit bioactive compounds, were postulated to have free radical-scavenging and apoptosis-inducing properties against certain types of cancers. Four highly purified limonoid glucosides, limoin 17beta D-glucopypranoside (LG), obacunone 17beta D-glucopyranoside (OG), nomilinic acid 17beta D-glucopyranoside (NAG), and deacetylnomilinic acid 17beta D-glucopyranoside (DNAG) were tested for superoxide radical (O(2)(-))-quenching activity and cytotoxic action against undifferentiated human SH-SY5Y neuroblastoma cells in culture. All 4 scavenged O(2)(-) as measured by inhibition of pyrogallol decomposition in a spectrophotometric assay. Quenching by NAG in particular emulated an equivalent concentration of vitamin C. When added to the medium of SH-SY5Y cells in culture, micromolar amounts of LG and OG, compared with untreated controls, caused a cessation of cell growth and rapid cell death (P < 0.001); NAG and DNAG were better tolerated, but nonetheless toxic as well. Cytotoxicity was related to a concentration- and time-dependent increase in caspase 3/7 activity, suggesting that limonoid glucosides were capable of inducing apoptosis. Arrested cell growth and the induction of apoptosis were confirmed by flow cytometry and DNA fragmentation analysis. Importantly, caspase induction at 12 h correlated with cell survival at 24 h (P = 0.046), suggesting that apoptosis was the primary cause of cell death. We conclude that citrus limonoid glucosides are toxic to SH-SY5Y cancer cells. Cytotoxicity is exerted through apoptosis by an as yet unknown mechanism of induction. Individual limonoid glucosides differ in efficacy as anticancer agents, and this difference may reside in structural variations in the A ring of the limonoid molecule.

Apoptosis↗
PubMed2005

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Bioethical Issues↗
PubMed2004

A requirement for copper in angiogenesis.

Although two decades have passed since copper was shown to stimulate blood vessel formation in the avascular cornea of rabbits, only recently have clinical trials established that Cu privation by diet or by Cu chelators diminishes a tumor's ability to mount an angiogenic response. These data have shed new light on the functional role of Cu in microvessel development and, of equal importance, stimulated new nutritional models of cancer therapeutic intervention.

Animals↗
PubMed2003

Pretranslational control of Menkes disease gene expression.

The gene for Menkes disease codes for a Cu-transporting ATPase that regulates Cu homeostasis in all tissues with the exception of adult liver. The basis for developmental or tissue-specific regulation at present is not understood. To learn if the regulation is associated with the promoter, we cloned and sequenced a 2.2 kb genomic DNA fragment flanking exon 1. When ligated into a pGL2 luciferase reporter gene construct, the 2.2 kb showed promoter activity, but not nearly to the extent of a 1.3 kb fragment previously reporter by Levinson et al. Sequence analysis of the nucleotides spanning the region between 1.3 kb and 2.2 kb revealed a 13-nucleotide motif ACACAAAAAAATA 2059 bp upstream from the start site that duplicated the 'hunchback' binding site, a key site controlling developmental gene expression in Drosophila. Eliminating 129 bp containing the hunchback site (Hb) from the 5' end of the 2.2 kb stimulated promoter activity, suggesting the Hb site was basically suppressive. When ligated upstream of an SV40 and tested in SY5Y cells, however, the SV40 promoter activity was strongly stimulated, which conflicts with the site being suppressive. Mutating the site in the 2.2 kb weakened the promoter activity in SY5Y and HepG2 cells and a fragment with mutated sequence ligated upstream of the SV40 cancelled the activation of SV40 promoter activity. All data suggested the Hb site was a positive controlling site for Cu-ATPase expression. Nuclear extracts from SY5Y and HepG2 cells were observed to bind to a 106 bp probe with the Hb site in a gel-shift assay. Only SY5Y proteins, however, showed a slower moving shift band indicative of a secondary interaction. A probe with mutated sequences displayed the same shift pattern, suggesting other sites in the 106 bp DNA strand were also recognizing the nuclear proteins. A Southwestern analysis suggested that proteins of 125 kD, 70 kD, 50 kD and 42 kD bound to the wild type probe; a 60 kD and all with the exception of the 42 kD bound to the mutant probe. The data support the conclusion that the distal promoter of the Menkes disease gene contains elements that interact in combinatorial fashion to regulate Cu-ATPase expression and that tissue specificity may lie with the quantity or types of distinct DNA binding proteins in the nucleus.

Adenosine Triphosphatases↗