Apc mutation induces resistance of colonic cells to lipoperoxide-triggered apoptosis induced by faecal water from haem-fed rats

International audienceRecent epidemiological studies suggest that high meat intake is associated with promotion of colon cancer linked with haem-iron intake. We previously reported that dietary haem, in the form of either haemoglobin or meat, promotes precancerous lesions in the colon of rats given a low-calcium diet. The mechanism of promotion by haem is not known, but is associated with increased lipid peroxidation in faecal water and strong cytotoxic activity of faecal water on a cancerous mouse colonic epithelial cell line. To better understand the involvement of faecal water components of haem-fed rats in colon-cancer promotion, we explored the effect of faecal water on normal [adenomatous polyposis coli (Apc)+/+] or premalignant cells (Apc-/+). Further, we tested if this effect was correlated to lipoperoxidation and 4-hydroxynonenal (HNE). We show here for the first time that heterozygote Apc mutation represents a strong selective advantage, via resistance to apoptosis induction (caspase 3 pathway), for colonic cells exposed to a haem-iron-induced lipoperoxidation. The fact that HNE treatment of the cells provoked the same effects as the faecal water of rats fed the haem-rich diet suggests that this compound triggers apoptosis in those cells. We propose that this mechanism could be involved in the promotion of colon carcinogenesis by haem in vivo

Steroidomimetic Tetrahydroisoquinolines for the Design of New Microtubule Disruptors

Structure–activity relationship translation offers an expeditious means for discovery of new active series. This approach was applied to discover tetrahydroisoquinoline (THIQ)-based steroidomimetic microtubule disruptors. The two A-ring elements of a three-point steroidal pharmacophore were incorporated into a THIQ-based A,B-ring mimic to which an H-bond acceptor was attached as the third motif. Optimization of the representative<b> 6c</b> through conformational biasing delivered a 10-fold gain in activity and a new series of microtubule disruptors (e.g., <b>9c</b>) with antiproliferative activity in the nanomolar range. The THIQ derivatives match, or surpass, the activities of the steroidal series and exhibit improved physicochemical properties

Chimeric microtubule disruptors

A chimeric approach is used to discover microtubule disruptors with excellent in vitro activity and oral bioavailability; a ligand-protein interaction with carbonic anhydrase that enhances bioavailability is characterised by protein X-ray crystallography. Dosing of a representative chimera in a tumour xenograft model confirms the excellent therapeutic potential of the class

Unit Publications - Bulletins, 2004-2005

The 2004-2005 School of Kinesiology bulletin provides information on undergraduate and graduate academic program requirements, course, and admission information. Also included is a course description document and a list of changes to the sports management courses.http://deepblue.lib.umich.edu/bitstream/2027.42/102604/1/Bulletin0405.ziphttp://deepblue.lib.umich.edu/bitstream/2027.42/102604/2/Courses0405.zi