Intrinsic death pathway

Two main apoptotic pathways have been identified in mammalian cells the extrinsic pathway that is activated by the binding of ligands to cell-surface death receptors, and the intrinsic pathway that involves the mitochondrial release of cytochrome cP The activation of extrinsic and intrinsic apoptotic pathways promotes the cleavage into the active form of the pro-caspase-8 and pro-caspase-9, respectively, that mainly determine the activation of effector caspase-3. ° The intrinsic pathway is the main apoptotic pathway activated by chemotherapeutic drugs, while the cytotoxic drug-induced activation of the extrinsic pathway is a more controversial issue. ... 

Increased activity of GSK-3/3 has been reported during neuronal degeneration (Beurel and Jope, 2006) and it has been associated with the promotion of the intrinsic mitochondrial pathway of apoptosis (Brazil and Hemmings, 2001). Pharmacological inhibition of GSK-3/3 reduces neuronal cell death caused by cerebral ischemia (Kelly et al., 2004), suggesting that prevention of GSK-3/3 activation may represent a potential approach to minimize neurodegeneration in the retina. 

Figure 1. Schematic of the apoplotic signaling pathways. The intrinsic apoptotic pathway consists of the mitochondrial pathway. The extrinsic pathway mediates apoptosis through activation of the death receptors, TNF-o/Fas receptors. Apoptosis is executed by activation of proteases, known as caspascs. ATP is essential for apoptosis. Bel-2 family proteins are apoptosis regulating proteins Bcl-2 inhibits while Bid, Bax, Bad facilitate apoptosis. An interaction between these two apoptotic pathways exists. See text for a more detailed explanation.

B-cell lymphoma 2 (Bcl-2) family members are regulators of the intrinsic apoptosis (programmed cell death) pathway, and anti-apoptotic family members have been strongly implicated in cancer [172]. Heterodimer-forming interactions between anti-apoptotic family members such as Bcl-xL or Bcl-2, and ot-helical domains of pro-apoptotic proteins control the ability of cells to carry out the apoptotic program. Several compounds have been reported to bind to and inhibit various anti-apoptotic Bcl-2 family members, but for most of these compounds reported affinities are poor, and structural information is unavailable [15]. 

Su and coworkers investigated the induction of apoptosis by Tan-I at 1-10 pg/mL in human colon cancer Colo 205 cells. Tan-I reduced cell growth in a concentration-dependent manner, inducing apoptosis accompanied by an increase in TUNEL-stained cells in the sub-Gl fraction. The treatment with Tan-I at 0, 1, 2.5, 5, and 10 pg/mL for 72 h increased the percentage of cells in sub-Gl phase from 3.83% to 7.22%, 8.68%, 14.4%, and 32.98%, respectively. The expression of p53, p21, bax, and caspase-3 increased in Tan-I-treated cells. The authors suggested that Tan-I induces apoptosis in Colo 205 cells through both mitochondrial-mediated intrinsic ceU-death pathways and p21-mediated GO/Gl cell cycle arrest [50]. 

Fig. 41.2 Cellular location and schematic representation of the apoptotic pathways activated by Berberine in tumor cells. Upper panels, berberine accumulates in the nucleus of A549 lung carcinoma cell line. Cells were incubated with berberine (50 pM) for the indicated times and, subsequently, nuclei were stained with the fluorescent dye DRAQ5. Images were taken in a Leica TCS SP2 confocal microscope. Pictures correspond to the central section in a confocal z-stack acquired sequentially. Green berberine Red DRAQ5 Grey DIC image. Lower panel, berberine activates in vitro the intrinsic cell death pathway. Berberine-induced apoptosis is initiated after DNA damage by cell cycle arrest in GO/Gl mediated by the ATM/p53 pathway. In addition, berberine is able to block cell cycle in G2M by activation the ATM/Chkl p53-independent pathway in some tumor cell types. Activation of these pathways leads to transcription (TF) of...

Berberine activates in vitro the intrinsic cell death pathway in several mouse and human tumor cell lines. Most of the studies suggest that berberine-induced... 

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