Time to tame necroptosis - viable combat against chemo resistant oral cancer cells

Till 1998, a little was known about alternative forms of regulated cell death beside apoptosis. In present scenario, accumulating evidences suggest a form of programmed necrosis called Necroptosis which can be induced by various external stimuli including anticancer drugs, ionizing radiation, photodynamic therapy in the form of death domain receptor (DR) engagement by their respective ligands, TNF-alpha, Fas ligand (FasL) and TRAIL, under apoptosis deficient condition (caspase inhibitor), etc. receptor interacting protein-1 (RIP-1), a death domain containing kinase is the key molecule in necroptotic cell death pathway. On interaction with an additional protein RIP-3 to form an intracellular complex (complex-IIb), it triggers the various downstream mechanisms of necroptosis which includes: i) excessive production reactive oxygen species (ROS) as RIP-3 interacts with metabolic enzymes (glycogen phosphorylase, glutamate dehydrogenase) which increases the concentration of substrates for oxidative phophorylation - a major source of ROS; ii) mitochondrial dysfunction (mitrochondrial permeability transition ). Necrostatin (Nec-1) and CYLD act as negative and positive regulators for this mode of cell death