The potential therapeutical effect of recombinant adenovirus mediated TRAIL transfection in lung cancer

THE POTENTIAL THERAPEUTICAL EFFECT OF RECOMBINANTADENOVIRUS MEDIATED TRAIL TRANSFECTION INLUNG CANCERÇ ĞDEM AYDIN ACARLung cancer causes the highest rate of cancer related deaths both in men andwomen. Currently, chemotherapy and radiotherapy are among the most commonlyused treatment modalities against lung cancer. Tumor supressor gene, p53, isrequired in order for both of these treatment methods to work as anti-tumor agents.As a result, tumors lacking p53 display resistance to both chemotherapy andradiotherapy. Death ligands such as TRAIL induce apoptosis regardless of p53 statusof cancer cells and are considered as potential therapeutic agents for gene therapy.However, TRAIL resistance observed in tumors including those of the lung seriouslychallenged any gene therapy approach targeting cancer. In addition, the mechanismof TRAIL resistance is not understood. On top of that, no correlation betweenTRAIL receptor expression profile and TRAIL resistance has been demonstrated incancer cells yet. In contrast, it is believed that no such correlation exists. In thisstudy, first we have tested adenovirus delivery of TRAIL as a potential gene therapymodality for patients with lung cancer. In our experimental settings, A549 lungcancer cell line displayed complete resistance to TRAIL induced cell death. Inaddition, a complementary gene therapy modality involving IKK inhibition(AdIKKβKA) sensitized lung cancer cell line (A549) to TRAIL. Second, TRAILreceptor composition of lung cancer cells was revealed by novel Real Time RT-PCRand flow cytometry analysis. Intriguingly, TRAIL resistance in A549 cell line wascorrelated with an increase in TRAIL-R4 decoy receptor expression on cell surface.Key Words: Lung cancer, adenovirus, gene therapy, TRAIL, IKK inhibition.