Combination of bladder cancer-specific oncolytic adenovirus gene therapy with cisplatin on bladder cancer in vitro

Abstract

Bladder cancer-specific oncolytic adenovirus Ad/PSCAE/UPII/E1A, carrying E1A gene regulated by human Uroplakin II (UPII) promoter and prostate stem cell antigen enhancer (PSCAE), could kill bladder tumor cells preferentially. The aim of this study was to examine the effects of Ad/PSCAE/UPII/E1A combined with cisplatin on human bladder cancer cells and to identify the underlying mechanisms. The combined effects of Ad/PSCAE/UPII/E1A and cisplatin on EJ, 5637, and BIU-87 bladder cancer cells were evaluated by MTT cell proliferation assay. Cell apoptosis was detected by flow cytometry with fluorescein isothiocyanate-conjugated annexin V (annexin V-FITC) and propidium iodide staining. The activation of the caspase pathway and the expression of Bcl-2 family proteins were determined by western blot assay. Ad/PSCAE/UPII/E1A adenovirus vector could infect bladder cancer cell lines selectively and induce growth inhibition effectively. Of note, the combination treatment of cisplatin and Ad/PSCAE/UPII/E1A could inhibit the proliferation of bladder cancer cells significantly compared with the "alone" treatment. Furthermore, Ad/PSCAE/UPII/E1A plus cisplatin combined treatment resulted in enhanced apoptosis in bladder cancer cells. The enhanced antitumor effects in vitro elicited by Ad/PSCAE/UPII/E1A plus cisplatin were closely related to the increased Fas expression and cleavage of caspase-8 and Bid and decrease in the ratio of anti- to pro-apoptotic proteins followed by activation of caspase-9 and caspase-3, which may contribute to the activation of extrinsic and intrinsic apoptotic pathways. Our results indicate that the combination of Ad/PSCAE/UPII/E1A with cisplatin exerts a synergistic antitumor effect on human bladder cancer cells and is a potential combined treatment strategy for bladder cancer.

Gene therapy targeting hepatocellular carcinoma by a dual-regulated oncolytic adenovirus harboring the focal adhesion kinase shRNA

“…In this study, we constructed double-regulated oncolytic adenovirus which proved to be a safe and efficient approach to suppress the development of AFP-positive liver cancer both in vitro and in vivo. Several promoters have been applied to achieve the selectivity for the tumor cells in the oncolytic systems, such as HRE, the prostate-specific antigen, osteocalcin, MUC1, midkine, lplastin, E2F-1, UPII and Survivin genes (30)(31)(32). The promoters of these reconstructed oncolytic adenoviruses can be only activated in certain tumor cells which produced the special transcription factor and finally resulted in massive virus replication.…”

A novel bladder cancer - specific oncolytic adenovirus by CD46 and its effect combined with cisplatin against cancer cells of CAR negative expression

“…Our previous study results suggest that combination of PSCAE with hUPII promoter is feasible in constructing bladder cancer-specific vectors [ 9 , 17 , 18 ]. Our oncolytic adenovirus exhibits bladder cancer-specific killing effect and exerts the synergistic antitumor effect with cisplatin on bladder cancer [ 9 , 10 , 18 , 19 ].…”

RGD-modifided oncolytic adenovirus exhibited potent cytotoxic effect on CAR-negative bladder cancer-initiating cells

“…Different types of adenoviruses were utilized and modified for gene transfer and targeted therapy on bladder cancer. 35 , 36 However, as for the emerging evidence of bladder CICs in bladder, it is important to find out efficient oncolytic adenoviruses targeting bladder CICs. We designed the RGD-modified oncolytic adenoviruses to overcome CAR deficiency in bladder cancer and examined their therapeutic potential on bladder CICs.…”