DƯỢC LÍ Goodman & Gilman's The Pharmacological Basis of Therapeutics 12th, 2010

pathways regulating apoptosis is important because
apoptosis plays an important role in normal cells and
because alterations in apoptotic pathways are implicated
in a variety of diseases such as cancer, and neurodegenerative
and autoimmune diseases (Bremer et al.,
2006; Ghavami et al., 2009). Thus, maintaining or
restoring normal apoptotic pathways is the goal of
major drug development efforts to treat diseases that
involve dysregulated apoptotic pathways (Fesik, 2005)
and selectively stimulating apoptotic pathways could
be useful in removing unwanted cells.
Two major signaling pathways induce apoptosis.
Apoptosis can be initiated by external signals that have
features in common with those used by ligands such as
TNF-α or by an internal pathway activated by DNA
damage, improperly folded proteins, or withdrawal of
cell survival factors (Figure 3-13). Regardless of the
mode of initiation, the apoptotic program is carried out
External
pathway
Inactive
Caspase 8
Extrinsic activating ligands
(TNF, Fas, TRAIL, etc.)
Active
Caspase 8
TNF, Fas, TRAIL
receptors
Death domain
TRADD/FADD
adaptors
+
+
Active
Caspase 3
+
Inactive
Caspase 3
Activation of
Caspases 6,7
by a large family of cysteine proteases termed caspases.
The caspases are highly specific cytoplasmic proteases
that are inactive in normal cells but become activated
by apoptotic signals (Danial and Korsmeyer, 2004;
Ghobrial et al., 2005; Strasser et al., 2000).
The external apoptosis signaling pathway can be activated by
ligands such as TNF, FAS (another member of the TNF family, also
called Apo-1), or the TNF-related apoptosis-inducing ligand
(TRAIL). The receptors for FAS and TRAIL are transmembrane
receptors with no enzymatic activity, similar to the organization of
the TNF receptor described above. They have large external ligandbinding
domains, short transmembrane domains, and a cytoplasmic
death domain capable of binding intracelllular adaptor proteins.
Upon binding TNF, FAS ligand, or TRAIL, these receptors form a
receptor dimer, undergo a conformational change, and recruit adapter
proteins to the death domain. The adaptor proteins are TNF-associated
death domain binding protein (TRADD), FADD, or TRAF2. These
adaptor proteins then recruit the receptor-interacting protein kinase
(RIP1) and caspase 8 to form a complex of RIP1, TRADD/
DNA damage
Active
Caspase 9
p53
activation
Cytochrome
C
Apaf-1
IAPs
+
Inactive
Caspase 9
APOPTOSIS
• DNA fragmentation
• Membrane blebbing
• Protein degradation
• Cell shrinkage
Cell membrane
Bax
+
Bcl-2
Exterior
Cytosol
Internal
pathway
67
CHAPTER 3
PHARMACODYNAMICS: MOLECULAR MECHANISMS OF DRUG ACTION
Figure 3–13. Two pathways leading to apoptosis. Apoptosis can be initiated by external ligands such as TNF, FAS, or TRAIL at specific
transmembrane receptors (left half of figure). Activation leads to trimerization of the receptor, and binding of adaptor molecules
such as TRADD, to the intracellular death domain. The adaptors recruit caspase 8, activate it leading to cleavage and activation of the
effector caspase, caspase 3, which activates the caspase pathway, leading to apoptosis. Apoptosis can also be initiated by an intrinsic
pathway regulated by Bcl-2 family members suc as BAX and Bcl-2. BAX is activated by DNA damage or malformed proteins via
p53 (right half of figure). Activation of this pathway leads to release of cytochrome c form the mitochondria, formation of a complex
with Apaf-1 and caspase 9. Caspase 9 is activated in the complex and initiates apoptosis thru activation of caspase 3. Either the extrinsic
or the intrinsic pathway can overwhelm the inhibitors of apoptosis proteins (IAPs) that otherwise keep apoptosis in check. See text
for details.