**2.1. Signaling pathways of apoptosis**

The classic apoptosis can be activated by the intrinsic and extrinsic pathways that both rely on the involvements of caspases [13]. To date, the signaling pathways of apoptosis have been well delineated and for the integrity of the present review, we only emphasize on the basic and major signal events of classic apoptosis. The mitochondria are the crucial converging site for the intrinsic and extrinsic signaling [14]. And specifically, mitochondrial outer membrane permeabilization (MOMP) serves as the key to initiate the final steps of apoptosis. MOMP results in the release of pro-apoptotic components of mitochondria, including cytochrome c, AIF, etc., and thereby the activation of subsequent apoptotic executive mediators [15]. MOMP can be regulated by BCL2 family proteins consisting of pro- and anti-apoptotic factors [10]. Bax and Bak are the main members of BCL2 family and serve as promoters for MOMP; Bcl-2 and Bcl-XL, in contrast, play just the opposite role. Notably, the balance between the two parts determines the fates of cells. In the intrinsic pathway, several cellular stresses including DNA damage, intracellular calcium overload and growth factor ablation can directly induce MOMP. In response to the release of cytochrome c, apoptosome consisting of caspase 9, Apaf-1 and cytochrome c is formed in plasma, which initiates the execution of apoptosis. In the extrinsic pathway, ligation of death receptors results in the formation of DISC, which recruits adapter proteins subsequently leading to combination of caspase-8/FLIP heterodimer and caspase-8 homodimer. The homodimer then cleaves effector proteins caspases-3, -6 and -7 and thereby finishes the execution of apoptosis [16]. It is worthy to note that the extrinsic pathway is able to amplify the apoptotic signals by initiating the intrinsic pathway through caspase-8-independent activation of tBid, which can cause MOMP [14].
