Oncotarget, 2016.

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

Effrosyni Tsafa, Mariam Al-Bahrani, Kaoutar Bentayebi, et al

Phage Therapy Group, Department of Medicine, Imperial College London, Hammersmith Hospital Campus, London, United Kingdom; Biotechnology Laboratory (Medbiotech), Medical and Pharmacy School, University Mohammed V de Rabat, Rabat, Morocco

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.

美国《肿瘤标靶》，2016

天然膳食金雀异黄素通过提高靶向肿瘤细胞转导来增强噬菌体介导的肿瘤细胞死亡

Effrosyni Tsafa, Mariam Al-Bahrani, Kaoutar Bentayebi, et al

噬菌体治疗组、 医学系、 伦敦大学帝国学院、 哈默史密斯医院校园，伦敦，英国;生物技术实验室 (Medbiotech)、 医疗及药剂学校，大学穆罕默德 V 德拉巴特，摩洛哥拉巴特

基因治疗长久以来一直被认为是有前途的治疗癌症的方法。然而，当通过临床可接受的非侵入性系统途径（即静脉内）施用时，肿瘤基因治疗仍面临靶向肿瘤基因特异性载体的挑战。细菌病毒，噬菌体 （噬菌体），代表了在全身基因传递中新一代有前途的载体，因为他们的目标可以实现通过噬菌体衣壳显示配体，使他们能够回到特定的肿瘤受体而不需要消除任何天然真核嗜性。我们先前报道了腺相关病毒/噬菌体或AAVP的肿瘤特异性噬菌体载体，其中下基因表达在通过配体定向噬菌体衣壳靶向肿瘤的重组人rAAV2病毒基。然而，用这种肿瘤靶向载体的癌症基因治疗实现了不同的结果，从肿瘤退化到实验和天然临床前模型中没有效果。在这里，我们假设组合天然饮食染料木素，与经验证的抗癌活性，将改善噬菌体抗癌安全治疗。我们表明与染料木黄酮和AAVP的组合治疗由AAVP携带单纯疱疹病毒胸苷激酶（HSVtk）在2D组织培养和3D肿瘤球体的基因增加靶向癌细胞杀伤力。我们发现这种增加的肿瘤细胞杀伤力与增强的AAVP介导的基因表达相关。接下来，我们建立了染料木黄酮保护AAVP抵抗蛋白酶体降解和增强核中的载体基因组积累。染料木黄酮和噬菌体引导的病毒疗法的组合是一种安全和有希望的策略，应该在使用AAVP的抗癌治疗中考虑。