Liu, K., Hearne, K., Mrsny, A., Staka, C. and Mrsny, R. J., 2012. A strategy to improve selectivity and targeting to epithelial-derived cancer cells. Journal of Controlled Release, 164 (2), pp. 205-212.
Examination of genomic and proteomic changes associated with ras-driven epithelial to mesenchymal transformation (EMT) of polarized epithelial cells has led to an improved understanding of surface-expressed structures and alterations in components involved in intracellular trafficking events that are altered as normal cells become cancerous. We have previously identified a mechanism involved in the establishment of tight junction (TJ) cell-cell contacts orchestrated by the protein occludin (Ocln) and its ability to reverse EMT events. Previous studies have suggested an increased functional expression of a cell-surface import system for small peptides, hPepT1, in several types of cancer cells. We now describe two approaches to identify agents capable of re-activating Ocln expression which could be modified into selective substrates of hPepT1. A screen for agents to re-activate suppressed occludin gene (OCLN) expression resulting from Ras/Raf/MEK/ERK pathway activation led to the identification of several small molecules. Using phage panning we have also identified several short peptide sequences that bind to the E-box used by the suppressor protein Slug to block OCLN expression. Thus, the current studies have identified several molecules and a roadmap to generate additional agents that could be examined for their ability to selectively enter cancer cells via hPepT1. We believe this strategy could result in reduced off-target drug distribution and thus greater functional targeting could be achieved for epithelial-derived cancers to prime them for the actions of established chemotherapeutic agents.
|Item Type ||Articles|
|Creators||Liu, K., Hearne, K., Mrsny, A., Staka, C. and Mrsny, R. J.|
|Departments||Faculty of Science > Pharmacy & Pharmacology|
|Publisher Statement||Mrsny_J_Controlled_Release_2012.pdf: NOTICE: this is the author’s version of a work that was accepted for publication in Journal of Controlled Release. Changes resulting from the publishing process, such as peer review, editing, corrections, structural formatting, and other quality control mechanisms may not be reflected in this document. Changes may have been made to this work since it was submitted for publication. A definitive version was subsequently published in Journal of Controlled Release, vol164, issue 2, 2012, DOI 10.1016/j.jconrel.2012.04.039|
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