title: In vivo histone H1 migration from necrotic to viable tissue.
abstract: Necrosis is induced by ischemic conditions within the core of many solid tumors. Using fluorescent fusion proteins, we provide in vivo evidence of histone trafficking among cancer cells in implanted tumors. In particular, the most abundant H1 isoform (H1.2) was found to be transported from necrotic tumor cells into surrounding viable cells where histones are selectively taken up by energy-dependent endocytosis. We propose that intercellular histone trafficking could function as a target for drug delivery. This concept was validated using an anti-histone antibody that was co-internalized with histones from dead cells into viable ones surrounding the necrotic regions of a tumor, where some of the most chemoresistant cells reside. These findings demonstrate that cellular translocation of conjugated drugs using anti-histone antibodies is a promising strategy for targeted drug delivery to chemoresistant tumors.
authors.affiliation: Allergan Inc., Irvine, CA, USA.|Previous address: Peregrine Pharmaceuticals Inc., Tustin CA, USA.
authors.forename: Keith A
authors.initials: KA
authors.lastname: Luhrs
authors.affiliation: Innovascreen Inc., Halifax, NS, Canada.|University of Alberta, Edmonton, AB, Canada.
authors.forename: Desmond
authors.initials: D
authors.lastname: Pink
authors.affiliation: Innovascreen Inc., Halifax, NS, Canada.
authors.forename: Wendy
authors.initials: W
authors.lastname: Schulte
authors.affiliation: Innovascreen Inc., Halifax, NS, Canada.|Vanderbilt University Medical Center, Nashville, TN, USA.
authors.forename: Andries
authors.initials: A
authors.lastname: Zijlstra
authors.affiliation: Innovascreen Inc., Halifax, NS, Canada.|University of Alberta, Edmonton, AB, Canada.
authors.forename: John D
authors.initials: JD
authors.lastname: Lewis
authors.affiliation: Rubicon Biotechnology, Lake Forest, CA, USA.|Previous address: Peregrine Pharmaceuticals Inc., Tustin CA, USA.
authors.forename: Missag H
authors.initials: MH
authors.lastname: Parseghian
mesh_terms: D000818:Animals; D016466:CHO Cells; D045744:Cell Line, Tumor; D002470:Cell Survival; D006224:Cricetinae; D003412:Cricetulus; D004705:Endocytosis; D006657:Histones / Q000378:metabolism*; D006801:Humans; D009336:Necrosis; D021381:Protein Transport
chemical_list: D006657:Histones
keywords: drug delivery; histone H1; necrosis; protein trafficking; tumor microenvironment