Role of Death Receptors Belonging to the TNF Family in Capsaicin-Induced Apoptosis of Tumor Cells

Capsaicin has been shown to induce apoptosis in various transformed cell types in vitro and in vivo. Apoptosis is triggered by an induction phase that is highly dependent on cell type and apoptogenic stimuli (e.g., death receptors, oxidative stress, DNA damage, ion fluctuations, and cytokines). This is followed by an effector phase where the cell undergo distinct biochemical changes as results of intrinsic mitochondrial-dependent and/or extrinsic death receptor-mediated apoptotic pathways. Depending on the concentration, duration of exposure and route of administration, CPS may either induce apoptosis in different cell types in a TRPV1-dependent and independent manner. It is generally accepted that CPS-mediated apoptosis is manifested by reactive oxygen species (ROS) generation, elevations in [Ca2+ ]i and mitochondrial transmembrane potential dissipation. However recent reports, indicate the ability of CPS to induce also up-regulation of Fas/CD95, TRAIL-R1/DR4, TRAIL-R2/DR5 and TNF-R1/DR1 death receptor expression, Fas Ligand-independent Fas-dependent TRPV1-mediated apoptosis of cancer cells, or to sensitize tumor cells to TRAIL-induced apoptosis. Unraveling the molecular mechanisms that underlie the CPS-induced targeting of death receptor in tumor cells and the death intracellular pathways activated by capsaicin, could provide the basis for novel therapeutic strategies in cancer patients.