Open AccessTargeted radiotherapy potentiates the cytotoxicity of a novel anti-human DR5 monoclonal antibody and the adenovirus encoding soluble TRAIL in prostate cancer
Author(s) -
Waleed Arafat,
Tong Zhou,
George E. Naoum,
Donald J. Buchsbaum
Publication year - 2015
Publication title -
journal of egyptian national cancer institute/journal of the egyptian national cancer institute
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.398
H-Index - 22
eISSN - 2589-0409
pISSN - 1110-0362
DOI - 10.1016/j.jnci.2015.08.003
Subject(s) - du145 , prostate cancer , lncap , medicine , cancer research , apoptosis , monoclonal antibody , programmed cell death , cancer , cancer cell , cell culture , cytotoxicity , prostate , antibody , in vivo , microbiology and biotechnology , immunology , biology , in vitro , biochemistry , genetics
TRAIL (tumor necrosis factor-related apoptosis-inducing ligand) induces a death signal following binding to death receptors (DR4, DR5). We have developed a novel anti-human DR-5 monoclonal antibody (TRA-8) and adenoviral encoding TRAIL (Ad/TRAIL). Herein, we are testing the combined effect of radiotherapy and TRA-8 or Ad TRAIL in prostate cancer cells. Human prostate cancer cell lines LnCap, PC-3 and DU145 were used in this study. Cells were treated either with TRA-8 alone or Ad/TRAIL, radiation alone, or a combination of each at different doses and intervals. Cell survival using the MTS assay and colony forming assay were used to determine radiosensitization. Immunohistochemistry was used to detect bax and bcl-2. Real-time PCR was performed on mRNA of treated prostate cancer cell lines. Finally, a murine model of subcutaneous prostate cancer was used to evaluate the in vivo effect. Cell survival assays detected by MTS assay showed that prostate cell lines treated with a combination of radiation and TRA-8 showed significantly lower survival than cells treated with either radiation or TRA-8 alone. Colony forming assay and cell proliferation assays showed increased killing after combination treatment with TRA-8 or Ad/TRAIL and radiation, than either single agent alone. Mechanistic studies showed that the killing effect was due to induction of apoptosis mostly by increased expression of bax in TRA-8 or Ad/TRAIL treated cells. Additionally, RT-PCR showed an increased copy number of bax in most cells treated with TRA-8 and radiation. It is concluded that radiation and TRA-8 or Ad/TRAIL produced a synergistic effect in refractory prostrate cancer.