The natural dietary genistein boosts bacteriophage-mediated cancer cell killing by improving phage-targeted tumor cell transduction
File(s)
Accepted version
Published version
Author(s)
Type
Journal Article
Abstract
Gene therapy has long been regarded as a promising treatment for cancer. However, cancer
gene therapy is still facing the challenge of targeting gene delivery vectors specifically to
tumors when administered via clinically acceptable non-invasive systemic routes (i.e.
intravenous). The bacteria virus, bacteriophage (phage), represents a new generation of
promising vectors in systemic gene delivery since their targeting can be achieved through
phage capsid display ligands, which enable them to home to specific tumor receptors without
the need to ablate any native eukaryotic tropism. We have previously reported a tumor
specific bacteriophage vector named adeno-associated virus/phage, or AAVP, in which gene
expression is under a recombinant human rAAV2 virus genome targeted to tumors via a
ligand-directed phage capsid. However, cancer gene therapy with this tumor-targeted vector
achieved variable outcomes ranging from tumor regression to no effect in both experimental
and natural preclinical models. Herein, we hypothesized that combining the natural dietary
genistein, with proven anticancer activity, would improve bacteriophage anticancer safe
therapy. We show that combination treatment with genistein and AAVP increased targeted
cancer cell killing by AAVP carrying the gene for Herpes simplex virus thymidine kinase
(HSVtk) in 2D tissue cultures and 3D tumor spheroids. We found this increased tumor cell
killing was associated with enhanced AAVP-mediated gene expression. Next, we
established that genistein protects AAVP against proteasome degradation and enhances
vector genome accumulation in the nucleus. Combination of genistein and phage-guided
virotherapy is a safe and promising strategy that should be considered in anticancer therapy
with AAVP.
gene therapy is still facing the challenge of targeting gene delivery vectors specifically to
tumors when administered via clinically acceptable non-invasive systemic routes (i.e.
intravenous). The bacteria virus, bacteriophage (phage), represents a new generation of
promising vectors in systemic gene delivery since their targeting can be achieved through
phage capsid display ligands, which enable them to home to specific tumor receptors without
the need to ablate any native eukaryotic tropism. We have previously reported a tumor
specific bacteriophage vector named adeno-associated virus/phage, or AAVP, in which gene
expression is under a recombinant human rAAV2 virus genome targeted to tumors via a
ligand-directed phage capsid. However, cancer gene therapy with this tumor-targeted vector
achieved variable outcomes ranging from tumor regression to no effect in both experimental
and natural preclinical models. Herein, we hypothesized that combining the natural dietary
genistein, with proven anticancer activity, would improve bacteriophage anticancer safe
therapy. We show that combination treatment with genistein and AAVP increased targeted
cancer cell killing by AAVP carrying the gene for Herpes simplex virus thymidine kinase
(HSVtk) in 2D tissue cultures and 3D tumor spheroids. We found this increased tumor cell
killing was associated with enhanced AAVP-mediated gene expression. Next, we
established that genistein protects AAVP against proteasome degradation and enhances
vector genome accumulation in the nucleus. Combination of genistein and phage-guided
virotherapy is a safe and promising strategy that should be considered in anticancer therapy
with AAVP.
Date Issued
2016-07-18
Date Acceptance
2016-06-16
Citation
Oncotarget, 2016, 7 (32), pp.52135-52149
ISSN
1949-2553
Publisher
Impact Journals
Start Page
52135
End Page
52149
Journal / Book Title
Oncotarget
Volume
7
Issue
32
Copyright Statement
© 2016 The Author(s). Published under a CC-BY licence 3.0 (https://creativecommons.org/licenses/by/3.0/)
License URL
Sponsor
Medical Research Council (MRC)
Brain Tumour Research Campaign
Grant Number
G0701159
N/A
Subjects
Science & Technology
Life Sciences & Biomedicine
Oncology
Cell Biology
bacteriophage display
genistein
cancer therapy
isoflavone
phage therapy
ADENOASSOCIATED VIRUS/PHAGE
PROTEASOME INHIBITORS
GENE-TRANSFER
TRANSGENE EXPRESSION
CYCLE ARREST
VECTORS
THERAPY
MECHANISM
DELIVERY
PROTEIN
Publication Status
Published