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.