Fig. 3.
Causal vs. accessory aspects of cell death from a therapeutic perspective. Cells exposed to very harsh environmental conditions disassemble in a virtually instantaneous and uncontrollable manner, a process that is referred to as accidental cell death (ACD). Conversely, relatively mild perturbations of exogenous or endogenous origin promote adaptative stress responses aimed at the restoration of cellular homeostasis. If such responses fail, cells generally activate one or more of multiple, highly interconnected signal transduction modules that precipitate regulated cell death (RCD). ACD cannot be retarded by pharmacological or genetic interventions, and most (if not all) strategies conceived so far to block RCD in mammalian organisms fail to efficiently do so, at least in part owing to the elevated interconnectivity of the process. Conversely, some agents that de facto promote RCD by primarily targeting the underlying molecular machinery (rather than by targeting normal cellular functions) are already available for use in the clinic. The events that follow primary cell death—including a secondary wave of RCD in neighboring cells established (directly or indirectly) by molecules released from the cells succumbing to the primary insult, as well as danger-associated molecular pattern (DAMP) signaling—may also be targets for pharmacological interventions. Finally, although altering quantitatively the percentage of cells succumbing to primary RCD remains challenging (especially when a hitherto poorly defined point-of-no-return of the process has been trespassed), favoring the use of specific signaling modules over others may have prominent effects on long-term disease outcome.