Selective inhibition of histone deacetylation in melanoma increases targeted gene delivery by a bacteriophage viral vector
File(s)cancers-10-00125.pdf (2.04 MB)
Published version
Author(s)
Hajitou, A
Campbell, S
Suwan, K
Waramit, S
Aboagye, E
Type
Journal Article
Abstract
The previously developed adeno-associated virus/phage (AAVP) vector, a hybrid between M13 bacteriophage (phage) viruses that infect bacteria only and human Adeno-Associated Virus (AAV), is a promising tool in targeted gene therapy against cancer. AAVP can be administered systemically and made tissue specific through the use of ligand-directed targeting. Cancer cells and tumor-associated blood vessels overexpress the αν integrin receptors, which are involved in tumor angiogenesis and tumor invasion. AAVP is targeted to these integrins via a double cyclic RGD4C ligand displayed on the phage capsid. Nevertheless, there remain significant host-defense hurdles to the use of AAVP in targeted gene delivery and subsequently in gene therapy. We previously reported that histone deacetylation in cancer constitutes a barrier to AAVP. Herein, to improve AAVP-mediated gene delivery to cancer cells, we combined the vector with selective adjuvant chemicals that inhibit specific histone deacetylases (HDAC). We examined the effects of the HDAC inhibitor C1A that mainly targets HDAC6 and compared this to sodium butyrate, a pan-HDAC inhibitor with broad spectrum HDAC inhibition. We tested the effects on melanoma, known for HDAC6 up-regulation, and compared this side by side with a normal human kidney HEK293 cell line. Varying concentrations were tested to determine cytotoxic levels as well as effects on AAVP gene delivery. We report that the HDAC inhibitor C1A increased AAVP-mediated transgene expression by up to ~9-fold. These findings indicate that selective HDAC inhibition is a promising adjuvant treatment for increasing the therapeutic value of AAVP.
Date Issued
2018-04-21
Online Publication Date
2018-04-21
2018-05-18T11:44:21Z
Date Acceptance
2018-04-19
ISSN
2072-6694
Publisher
MDPI AG
Journal / Book Title
Cancers
Volume
10
Issue
4
Copyright Statement
© 2018 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access
article distributed under the terms and conditions of the Creative Commons Attribution
(CC BY) license (http://creativecommons.org/licenses/by/4.0/).
article distributed under the terms and conditions of the Creative Commons Attribution
(CC BY) license (http://creativecommons.org/licenses/by/4.0/).
Source Database
manual-entry
Sponsor
Medical Research Council (MRC)
Grant Number
G0701159
Subjects
C1A
HDAC inhibitors
HDAC6
bacteriophage
targeted cancer gene therapy
Publication Status
Published
Article Number
125