No abstract

Activation of the Wnt/B-catenin signaling pathway occurs in several types of cancers and thus it is an attractive target for anticancer drug development. To identify compounds that inhibit this pathway, we screened a chemical library using a cell-based B-catenin/Tcf -responsive reporter. We identified FH535, a compound that suppresses both Wnt/B-catenin and peroxisome proliferator -activated receptor (PPAR) signaling. FH535 antagonizes both PPAR; and PPARD ligand -dependent activation and shows structural similarity to GW9662, a known PPAR; antagonist. The effect of FH535 on B-catenin/Tcf activity is reduced in cells carrying a deletion of the PPARd gene, as well as by the PPAR; agonist lysophosphatidic acid. Mechanistically, FH535 inhibits recruitment of the coactivators B-catenin and GRIP1 but not the corepressors NCoR and SMRT. Its repression of B-catenin recruitment, in comparison with GW9662, is linked to FH535 ¶s unique capability to inhibit the Wnt/B-catenin signaling pathway. The antiproliferation effect of the compound observed on some transformed colon lung and liver cell lines is suggestive of its potential therapeutic value in the treatment of cancer. [Mol Cancer Ther 2008;7(3):521 -9]

No abstract

Malarial parasites reproduce asexually inside the erythrocytes of their vertebrate host. Relatively little is known about the interaction between host cell and parasite metabolism. In the present study the effect of host cell cation composition and osmotic shrinkage on in vitro growth and propagation of Plasmodium falciparum in human erythrocytes was investigated. It is shown that throughout the parasite cell cycle, infected cells lose potassium and gain sodium. Compartment analysis of infected cells revealed that host cell cytosol is poor in potassium and rich in sodium while in the parasite this relationship is reversed, indicating that the parasite is able to regulate its ionic composition independently. Parasites proceeded normally through their cell cycle in the presence of the sodium-pump inhibitor ouabain, although host cells lost up to 75-80% of their normal potassium content. Potassium-depleted erythrocytes harboring trophozoites and schizonts also display normal rates of protein synthesis as measured by isoleucine incorporation. Parasite growth was inhibited when infected cells were osmotically shrunken in hypertonic media, but this was not due to parasite dehydration. It is suggested that increased viscosity of host cell cytosol and/or hemoglobin gelation, are responsible for the effect, probably through interference with parasite feeding. The relevance of these results to understanding of the cellular mechanism involved in the inhibiton of parasite growth in deoxygenated sickle-trait erythrocytes is discussed.