The natural dietary genistein boosts bacteriophage-mediated cancer cell killing by improving phage-targeted tumor cell transduction

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.

Let-7d increases ovarian cancer cell sensitivity to a genistein analog by targeting c-Myc

“…DFOG is a novel synthetic genistein analogue that exerts anti-ovarian cancer effects by suppressing tumor stemness [ 8 - 10 ]. In the present study, we observed that knocking down c-Myc greatly sensitized ovarian cancer cells to DFOG.…”

“…Immunohistochemistry was carried out as described previously [ 10 ] using a rabbit anti-human c-Myc polyclonal antibody (1:100 dilution; Santa Cruz Biotechnology, USA). Sections were stained using DAB, counterstained with hematoxylin, mounted in neutral gum, and visualized using a bright field microscope.…”

“…Genistein (GEN) is a natural isoflavone in fruits, nuts, soybeans, and soy-based products. It induces cell apoptosis and cell cycle arrest in various cancer cells [ 8 - 10 ]. DFOG (7-difluoromethoxyl-5,4’-di-n-octylgenistein) is a novel synthetic genistein analogue that exhibits potent anticancer activity.…”

Drug delivery vectors based on filamentous bacteriophages and phage-mimetic nanoparticles

“…Moreover, in order to improve anticancer safety therapy of AAVP system, this system was further modified by combining AAVP together with natural dietary genistein which had anticancer activity, and the results showed increased cell killing. (Tsafa et al, 2016).…”

Mechanism study of isoflavones as an anti-retinoblastoma progression agent

“…Several studies have demonstrated that in vitro , genistein could prohibit the growth of various cancer cell lines including breast cancer cells [ 11 ], lung cancer cells [ 12 ], and colorectal cancer cells [ 9 ]. In addition, genistein could boost bacteriophage-mediated cancer cell killing [ 13 ]. Isoflavones are also helpful in the treatment of certain cancers by inhibiting tyrosine kinase activity and regulating Akt, mitogen-activated protein kinase and other signalling pathways [ 13 - 17 ].…”