Sensitisation of cancer cells to TRAIL using a cFLIP inhibitor

Cancer is often used as a broad term to describe over 277 variant types of the disease. The progress of which is thought to be due to genetic changes (Hasspour & Dehghani 2017). Research showed fundamental key characteristics that defined how cancer cells behave. These were condensed into eight key traits summarised as self- sufficiency from growth signals, insensitivity to growth signal factors, evading apoptosis, limitless replicative ability, continuous angiogenesis, metastatic activity, escaping the immune response and reprogramming metabolism. Apoptosis is a mechanism that triggers a cellular programme leading to cell death. There are two main modes of apoptosis, the extrinsic and the intrinsic signal transduction pathways. The extrinsic pathway, triggered by death ligands such as TRAIL, contains many proteins such as death receptors and eventually culminates in Caspase-8 and -10 initiating a downstream caspase cascade. There are however other proteins such as FLIP that can inhibit apoptosis triggered by death ligands. As FLIP is often overexpressed in cancer cells, compounds that can block its anti-apoptotic effect hold great promise. In this study a new inhibitor of FLIP was tested alone and in combination with TRAIL. Cell survival was measured with a Crystal Violet assay after treatment with FLIPi alone, recombinant TRAIL alone or a combination. Apoptosis was measured using a DNA hypodiploidy (Nicoletti) assay It was found that that cancer cells showed some cytotoxicity in response to the FLIPi, but the FLIP inhibitor did not induce apoptosis. Some cancer cells, such as colorectal cancer HCT116 cells and advanced prostate cancer cells C4-2B could be sensitised to TRAIL by the FLIP inhibitor, while others could not. The molecular reasons for this heterogeneity must be elucidated before a combination of TRAIL and FLIP inhibitor can be progressed further.