Potent growth-inhibitory effect of a dual cancer-specific oncolytic adenovirus expressing apoptin on prostate carcinoma

Abstract

Apoptin is a chicken anemia virus-derived, p53-independent, bcl-2-insensitive apoptotic protein with the ability to specifically induce apoptosis in various human tumor cells, but not in normal cells. To explore the use of apoptin in tumor gene therapy, we assessed a recombinant adenovirus expressing the apoptin protein (Ad-hTERTp-E1a-Apoptin) in order to determine its lethal and growth-inhibitory effects on PC-3 and RM-1 cells in vitro and its antitumor effect on solid tumors in vivo. 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide (MTT), acridine orange (AO)/ethidium bromide (EB), 4'-6-diamidino-2-phenylindole (DAPI), and Annexin V assays showed that Ad-hTERTp-E1a-Apoptin inhibited the proliferation of PC-3 and RM-1 cells in vitro by inducing apoptosis of prostate cancer cells, and that this inhibitory effect was dose and time-dependent. In the animal models, Ad-hTERTp-E1a-Apoptin significantly inhibited tumor growth and extended the lifespan of animals. Experimental results indicate that Ad-hTERTp-E1a-Apoptin has a potential application in tumor gene therapy.

Chemovirotherapy of Lung Squamous Cell Carcinoma by Combining Oncolytic Adenovirus With Gemcitabine

“…For the melanoma A375 and B16 cell lines, the infection with the adenoviruses expressing apoptin were observed predominantly in a late apoptotic stage. Also, Ad-VT conferred significant survival benefits in vivo (29)(30)(31)(32). The mice lungs infected with Ad-VT had minimal metastatic nodules; whereas, the lungs from control or treated groups had severe metastasis.…”

“…NCI-H226 cells (1 × 10 7 /100 µL) were injected into the right hind leg of nude mice. The xenograft models were infected with Ad-VT (1 × 10 9 plaque forming unit, PFU; biweekly) via intratumor injection and gemcitabine (30,60, and 120 mg/Kg; weekly) via intraperitoneal injection. The length and width of the xenograft tumors were weekly measured using a vernier caliper.…”

“…Ad-Apoptin-hTERTp-E1a (Ad-VT), that allows the adenovirus to selectively identify cancer cells, proliferate in large numbers, expresses the apoptin protein, and trigger tumor cell death (28). We showed that the modified adenovirus has a significant killing effect on several tumor cells (29)(30)(31)(32). Another study evaluated the preclinical safety of Ad-VT and demonstrated that it has no obvious adverse effects on the central nervous, cardiovascular, respiratory or gastrointestinal systems (31).…”

Viral genes as oncolytic agents for cancer therapy

“…Apoptin in a protein form with transduction tags as a fusion protein has also been tried. [179,180]. Another study that employed a conditionally replicating adenovirus carrying apoptin demonstrated an inhibitory effect on melanoma cells, and suppressed both subcutaneous primary tumor as well as lung metastatic tumors [181].…”

On Advances in Cancer Suicide-genes Therapy

“…This allows a specific induction of apoptosis in cancer cells. [47] This ability to kill only tumor cells has been reported in breast [48] , head and neck [49] , prostate [50,51] , lung cancer, osteosarcoma [50] , hepatocellular [52] and nasopharyngeal [53] carcinoma. A study analyzed the ability to induce apoptosis of five truncated apoptin proteins in human breast adenocarcinoma MCF-7 cells and human liver Chang cells as control.…”