Photochemically mediated delivery of AdhCMV-TRAIL augments the TRAIL-induced apoptosis in colorectal cancer cell lines.
Tumor targeting is an important issue in cancer gene therapy. We have developed a light-specific transduction method, named photochemical internalization (PCI), to enhance gene expression from adenoviral vectors selectively in illuminated areas. Tumor necrosis factor related apoptosis inducing ligand (TRAIL) has been shown to induce apoptosis in cancer cells, and the aim of this study was to investigate the potential of PCI to enhance transgene expression from AdhCMV-TRAIL and evaluate its impact on apoptotic induction in the two human colorectal cancer cell lines HCT116 and WiDr. PCI-mediated delivery of AdhCMV-TRAIL enabled an increased expression of TRAIL, induced a synergistic reduction in cell viability compared to the individual action of AdhCMV-TRAIL and photochemical treatment, and enhanced the induction of apoptosis demonstrated by an increase in cytoplasmic histone-associated DNA fragments, caspase-8 and caspase-3 activation, PARP cleavage and a decrease in the mitochondrial membrane potential. The synergistic effect could be related to the enhanced TRAIL expression in PCI-treated samples and a modest sensitization of the cancer cells to TRAIL induced apoptosis due to the photochemical treatment. Furthermore, an increased cleavage of Bid and a cell line dependent reduction in the expression levels of anti-apoptotic Bcl-2 family members were observed and could possibly contribute to the enhanced apoptotic level in samples exposed to the combined treatment. The presented results indicate that photochemically mediated delivery of AdhCMV-TRAIL allows a selective enhancement in cell killing, and suggest that PCI may be relevant and advantageous for therapeutic gene delivery in vivo.
Engesaeter
Birgit Ø
BØ
Department of Tumor Biology, Rikshospitalet-Radiumhospitalet Medical Center, Montebello, Oslo, Norway.
Bonsted
Anette
A
Lillehammer
Trine
T
Engebraaten
Olav
O
Berg
Kristian
K
Maelandsmo
Gunhild M
GM
D000256:Adenoviridae / Q000235:genetics; D017209:Apoptosis; D045744:Cell Line, Tumor; D002470:Cell Survival; D015179:Colorectal Neoplasms / Q000473:pathology*; D003587:Cytomegalovirus / Q000235:genetics; D005822:Genetic Vectors; D006801:Humans; D008940:Mitotic Index; D010777:Photochemistry; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000235:genetics / Q000502:physiology* / Q000627:therapeutic use*
D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human