Page 987 - Hematology_ Basic Principles and Practice ( PDFDrive )

870 Part VII Hematologic Malignancies

or DNA damage, they do not directly interact with the intracellular metabolic stimuli. A number of current anticancer agents in develop-
machinery involved in apoptosis. Tumor selectivity of conventional ment target these pathways and are designed to be effective alone or
agents is largely caused by the increased sensitivity to apoptosis of in combination with other agents that disrupt the cell cycle, DNA
tumor cells after DNA damage or cell cycle perturbation. Novel synthesis, invoke DNA damage, and so on.
therapeutic agents or strategies that target critical regulators or effec-
tors of apoptosis are under development and clinical testing, and
these agents or strategies have the potential to exert selective cytotox- Death Receptor–Initiated Apoptotic Signaling
icity against cancer cells.
Caspases are the “executioners” for apoptosis. They are proteases Several TNF family receptors are known to transduce signals that
that exist as inactive zymogens and are activated by proteolytic cleav- result in apoptosis. These include TNFRSF1A (also known as
age of their proforms in response to a variety of death stimuli. This CD120a and previously designated tumor necrosis factor receptor-1
processing occurs at conserved aspartic acid residues, thus generating [TNFR1]), TNFRSF6 (also known as CD95, APO-1, or FAS),
the enzymatically active caspases. Caspase activation is organized as TNFRSF25 (also designated TRAMP and known as DR3 or APO3),
a cascade, with an upstream initiator and downstream effector TNFRSF10A (also known as DR4 or TRAIL-R1), and TNFRSF10B
caspase. Upstream initiator caspases contain large prodomains that (also known as DR5 or TRAIL-R2). These receptors, also called death
interact with specific proteins involved in triggering the cascade. The receptors, are characterized by the presence of a death domain within
downstream caspases, which function as the ultimate effectors of their cytoplasmic region, and have been shown to trigger apoptosis
apoptosis, possess small prodomains and are activated predominantly upon binding to their cognate ligands or specific agonist antibody.
by proteolytic cleavage by upstream caspases. The irreversible cleavage The activating ligands for these death receptors are structurally related
of specific protein death substrates by the downstream effector cas- molecules that also belong to the TNF gene superfamily such as
pases directly or indirectly accounts for the biochemical and morpho- TNFSF6 (also known as Fas ligand), TNF, and TRAIL.
logic changes that are recognized as apoptosis. Ligation of death receptors produces receptor trimerization and
At least three pathways of caspase activation leading to apoptosis formation of a death-inducing signaling complex (DISC). This is
have been identified (Fig. 57.9): (1) the receptor-initiated apoptosis composed of TNFRSF6, Fas (TNFRSF6)-associated via death
pathway, where the TNF family of cytokine receptors activate initia- domain (FADD), and procaspase 8, an apical signaling complex that
tor caspases such as caspase 8; (2) the mitochondria-initiated apoptosis mediates receptor-induced apoptosis. FADD binds directly to FasR,
pathway, where cyt c and other prodeath effectors are released from TNFRSF10A, or TNFRSF10B and indirectly to TNFRSF1A via
mitochondria into the cytosol that results in activation of caspase 9; TNFRSF1A-associated via death domain protein (TRADD). FADD
and (3) a pathway of caspase activation, which involves a serine is essential for cell death signaling from all three receptors. FADD
protease, granzyme B, that directly cleaves and activates several cas- interacts through its C-terminal death domain to cross-link
pases, including procaspase 3. TNFRSF6, TNFRSF10A, or TNFRSF10B receptors and recruits
procaspase 8 and procaspase 10, or TRADD, through its N-terminal
death effector domain (DED) to the DISC (see Fig. 57.9). Oligo-
Proapoptotic Targets of Anticancer Agents merization of caspase 8 within the DISC results in a high local
concentration of the zymogen. The induced proximity under these
Most cancer cells have active antiapoptotic pathways that prevent cell crowded conditions generates low levels of intrinsic proteolytic activ-
death in response to growth, checkpoint, DNA damage, and ity of caspase 8, enough to allow the various proenzymatic molecules

Apo-21/TRAIL/FASL
Apoptotic stimuli
(anticancer agents) Death receptor

Bim, PUMA
Noxa, BAD Bax,Bak
Bcl-2
Bcl-x L FADD
FLIP DISC
Procaspase-8
Bcl-2 tBid
Bcl-x L
Mcl-1
Bid
Omi/HtrA2,SMAC Cytochrome c Caspase-8
+
Apaf-1/caspase-9/dATP

IAPs Caspase-3
AIF
Endonuclease G
Cellular targets

DNA Apoptosis
fragmentation

Fig. 57.9 SCHEMATIC REPRESENTATION OF APOPTOTIC PATHWAYS.