The kiss of death.

The kiss of death Cellular suicide is a grave matter, motivating researchers to a thorough exploration of the genetic pathways involved. Of the three main means by which cells die, most in the scientific community are quite familiar with the genetically regulated apoptotic pathway (1). Autophagy, in which the cell literally digests itself, is likewise now also recognized as a form of regulated cell death (2). However, the third member of the cellular death triad, necro-sis, has generally been considered merely an unregulated — accidental — form of cellular death. But there has been increasing evidence that cells may in fact choose, in a programmed genetic fashion, to take their lives via necrosis as well (3). Now Zong et al. provide solid data making it clear that the idea that necrosis can be a regulated pathway is, indeed, " dead to rights " (4). Here, the researchers show a necrotic form of cellular death that is completely independent of the main apoptotic effectors but that has an absolute requirement for activation of the DNA repair protein poly(ADP-ribose) polymerase (PARP). Activation of PARP is not, however, sufficient for this suicidal pathway; for necrosis to be instigated, the cell must also rely primarily on glycolysis for energy production. Craig Thompson, a University of Penn-sylvania researcher and senior author of the article by Zong et al., additionally noted that this work may provide potential insight into some paradoxical aspects of how cancer therapies work and create novel directions for cancer therapy. " During carcinogenesis there is a drive in the cancer cells to acquire mutations that render them resistant to apoptosis, " Thompson told the JCI. " Despite that, there has also been a lot of evidence, mostly by studying normal cells, that one way that cells deal with chemotherapeutic agents is by initiating apoptosis. " Thus, the paradox is as follows: if cancer cells are more resistant to apoptosis than are normal cells, how is it that a purportedly apoptosis-inducing drug can be an effective anticancer agent? " That suggested to us that chemotherapy must have some mechanism to initiate cell death even in cells that were resistant to apoptosis, " Thompson said. Testing several chemotherapeutic agents on laboratory-generated apoptosis-resistant cells, they found that alkylating agents, one of the chemotherapeutic agents with historically the longest use, killed these cells just as effectively as normal cells and did it through this regulated necrotic …