The cutting edge: apoptosis and therapeutic opportunity - Artificial Cells, Cell Engineering and Therapy - page 120

Cell death caused by radiation, chemotherapy, oxidative stress and DNA-
damaging agents induce apoptosis through the mitochondrial permeabilization
mediated intrinsic pathway. Anti-apoptotic proteins of the Bcl-2 family, such as
Bcl-2 and Bcl-X L , stabilize mitochondria and prevent its permeabilization by
neutralizing or titrating-out pro-apoptotic proteins like Bax, also a member of
the Bcl-2 family.
Identification of the key players of apoptosis, including several death recep-
tors, initiator and executioner caspases, pro- and anti-apoptotic Bcl-2 family
proteins, cytochrome c and certain nucleases, provides a great opportunity to
design modulators for diseases that involve apoptosis (Hu and Kavanagh, 2003).
Currently there is an unprecedented amount of interest in this relatively young
field of research. Development of modulators against the aforementioned targets
in order to activate apoptosis selectively in cancer cells and inhibit apoptosis in
post-mitotic cells to prevent progression of neurodegenerative diseases and
immune cell depletion in HIV patients (Reed, 2002), has become a major focus
in research today. A brief description of some of these diseases in light of
involvement of apoptosis and the therapeutic opportunities is described in the
sections below.

5.2 Apoptosis and neurodegeneration
Throughout the development of the central nervous system, induction of cell
death is not uncommon as many excess cells and those developing improperly
are eliminated by apoptosis (Lindsten et al., 2003). However, serious problems
arise when apoptosis occurs after development has been completed, resulting in
the loss of vital post-mitotic cells such as neurons and cardiac muscle cells as is
the case for multiple neurodegenerative as well as cardiovascular disease,
including stroke and cardiac arrest.

5.3 Cell death during stroke

Though the biochemical makeup of brain and heart muscle cells is quite
different, the effects of ischemia as it occurs in both organs during stroke and
cardiac arrest respectively are comparable. In cases of stroke, neurons directly
devoid of blood flow, found in the core region, are killed within minutes of this
effect, while neurons in the surrounding region termed the penumbra retain their
potential for survival for hours or even days. Specifically, this latter region can
be saved by reperfusion when blood flow is returned, however, this is certainly
not without consequences (Cuzzocrea et al., 2001). As blood supply is returned,
this reperfusion stage is linked to a massive increase in reactive oxygen species
(ROS) as a result of the altered function of the mitochondria's electron transport
chain which can directly and indirectly trigger apoptotic cell death (Adhihetty
and Hood, 2003). The ROS-mediated pathway is involved in apoptosis in