, 2008). Herein, all molecules assessed induced caspases activation, with intensification in early and late apoptotic processes. The phosphatidylserine externalization induced at 2 μM is an additional finding that corroborates activation of pathways suggestive of apoptosis. Loss of membrane polarity, Dapagliflozin mw caused by translocation of phosphatidylserine from the inner to outer plasma membrane, thereby exposing phosphatidylserine for

external environment, stimulates recognition and engulfment of dying cells by macrophages and other antigen presenting cells (Kroemer et al., 1997). In order to improve comprehension about cell signaling, it was performed a mitochondrial depolarization analyses. Apoptosis stimulation by the mitochondrial

via starts with a pore formation in the external membrane mitochondrial and release of cytochrome c, with permeability changes and mitochondrial membrane potential collapse. This failure can be measured by cationic lipophilic fluorochromes, such as rhodamine 123 ( de Thonel and Eriksson, 2005). Within 24 h of treatment, α-santonin derivatives GSK1120212 molecular weight did not induce modifications in mitochondrial potential. However, following 48 h, the compound 4 induced mitochondrial depolarization, an indicative of apoptosis intrinsic pathway activation commonly caused in reaction to DNA damage, absence of survivor factors and several types of cellular stress. Whereas caspase-8 was activated, it is likely that it had been occurred

convergence into apoptosis intrinsic pathway downstream from the extrinsic route. Costunolide, a sesquiterpene lactone structure close to α-santonin, induces G2/M cell cycle arrest and cause apoptosis on several cell tumor lines through extrinsic pathway before intrinsic activation, leading to the caspase-8 Bid stimulation, a pro-apoptotic protein belonging to BCL-2 family that Mannose-binding protein-associated serine protease also activates mitochondrial pathways ( Liu et al., 2011). This indirectly mitochondrial involvement could explain a longer extensive interval required (48 h) by α-santonin derivatives 2 and 4 to instigate cell damage, which culminates with mitochondrial depolarization and DNA destabilization ( de Thonel and Eriksson, 2005, Liu et al., 2011, Choi et al., 2012 and Guzman and Jordan, 2005). Sesquiterpene lactones have a privileged selectivity for tumor cells (Ghantous et al., 2010). Previously, compounds 2, 3 and 4 were tested against normal cells (PBMC) and showed low toxicity (Arantes et al., 2010). Here, the same ones were tested in alkaline comet assay to analyze their ability to cause DNA alkylation on PBMC. None of compounds were able to DNA disruptions in both concentrations tested (data not shown). Similarly, it was displayed that Parthenolide, another sesquiterpene lactone, selectively kill primitive leukemia cells without affecting normal stem and progenitor hematopoietic cells (Guzman and Jordan, 2005).