A strategy to improve selectivity and targeting to epithelial-derived cancer cells

K Liu, K Hearne, Adrienne Mrsny, C Staka, Randall J Mrsny

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Abstract

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.
Original languageEnglish
Pages (from-to)205-212
Number of pages8
JournalJournal of Controlled Release
Volume164
Issue number2
Early online date1 May 2012
DOIs
Publication statusPublished - 10 Dec 2012

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Occludin
Neoplasms
Epithelial-Mesenchymal Transition
Gene Expression
Peptides
Gastropoda
MAP Kinase Signaling System
Tight Junctions
Proteomics
Bacteriophages
Proteins
Epithelial Cells
Pharmaceutical Preparations

Cite this

A strategy to improve selectivity and targeting to epithelial-derived cancer cells. / Liu, K; Hearne, K; Mrsny, Adrienne; Staka, C; Mrsny, Randall J.

In: Journal of Controlled Release, Vol. 164, No. 2, 10.12.2012, p. 205-212.

Research output: Contribution to journalArticle

Liu, K ; Hearne, K ; Mrsny, Adrienne ; Staka, C ; Mrsny, Randall J. / A strategy to improve selectivity and targeting to epithelial-derived cancer cells. In: Journal of Controlled Release. 2012 ; Vol. 164, No. 2. pp. 205-212.
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