Oncotarget

Research Papers:

In vivo histone H1 migration from necrotic to viable tissue

Keith A. Luhrs, Desmond Pink, Wendy Schulte, Andries Zijlstra, John D. Lewis and Missag H. Parseghian _

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Oncotarget. 2017; 8:16275-16292. https://doi.org/10.18632/oncotarget.15181

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Abstract

Keith A. Luhrs1,6, Desmond Pink2,4, Wendy Schulte2, Andries Zijlstra2,3, John D. Lewis2,4 and Missag H. Parseghian5,6

1 Allergan Inc., Irvine, CA, USA

2 Innovascreen Inc., Halifax, NS, Canada

3 Vanderbilt University Medical Center, Nashville, TN, USA

4 University of Alberta, Edmonton, AB, Canada

5 Rubicon Biotechnology, Lake Forest, CA, USA

6 Previous address: Peregrine Pharmaceuticals Inc., Tustin, CA, USA

Correspondence to:

Missag H. Parseghian, email:

Andries Zijlstra, email:

John D. Lewis, email:

Keywords: tumor microenvironment, drug delivery, histone H1, protein trafficking, necrosis

Received: January 20, 2017 Accepted: January 25, 2017 Published: February 07, 2017

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.


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PII: 15181