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.