Membrane-Related Diseases - Membrane Biophysics, Biological and Medical Physics, Biomedical Engineering - page 153

naling through AKT activation stimulates phosphorylation of BAD, which allows
B-cell lymphoma (BCL 2) protein (encoded by the BCL2 gene) to exert its anti-
apoptotic effects by blocking pro-apoptotic proteins NOXA, BAX, etc. However,
dephosphorylated BAD blocks BCL2 by hetero-dimerization (BAX/BCL2), which
allows pro-apoptotic proteins to form pores in the mitochondria. This process then
releases apoptogenic factors from the mitochondrial inter-membrane space, includ-
ing cytochrome C (Cyt C), APAF1, and caspase 9. These factors form the so-called
apoptosome, which stimulates apoptosis through caspase 3 cleavage. Conventional
studies have shown the BCL 2 protein family is one group of gene products that
governs the initial phase of apoptosis [ 42 ]. Both anti-apoptotic (BCL 2 protein) and
pro-apoptotic (BAX) family members, whose crystal structures have been experi-
mentally determined [ 32 , 33 , 43 ], are potential drug targets in cancer treatments
[ 31 ]. The multiple sequence alignment for six BCL 2 family proteins presents com-
mon motifs among these proteins [ 33 ]. Two potent small-molecule inhibitors (ABT-
737 and ANT-263) designed to inhibit BCL 2/BCL-xL proteins have been described
recently [ 31 , 46 , 48 ]. This inhibition is likely to help overcome the BCL 2 protein-
induced anti-apoptosis activity [ 46 ]. A strategic study can be suggested for apop-
tosis modulation in cancer treatment by considering an appropriate combination of
“regulators”. The regulators would act at different proteins which are responsible
for triggering and/or inhibiting apoptosis. Here specifically we can consider a set of
regulators consisting of inhibitors for BCL 2 protein (anti-apoptosis) and enhancers
for BAX's pro-apoptosis effect. The modulation of cancer treatment, however, can
be monitored looking at the lipid functions in membranes.
For diagnostic purposes, the redistribution of PS between inner and outer plasma
membranes (Fig. 7.1 ) should be considered, as recently described in detail [ 27 ], (PS
externalization), which has been shown as an early marker of apoptosis. PS exter-
nalization is specific to apoptotic cells with the exception of activated platelets and
erythrocytes. PS externalization, therefore, is an attractive target to detect apoptosis
[ 9 , 10 , 40 ] and to provide an early indication of the success or failure of therapy for
cancer patients in a clinical setting. Lahorte et al. [ 23 ] provides a thorough overview in
apoptosis-detecting radiotracers. Currently, annexin V is considered to be the most
promising agent in clinical applications [ 49 ]. Several groups have prepared 18F
labeled annexin V by different approaches to be used with positron emission tomog-
raphy (PET) because of its higher resolution and more quantitative imaging [ 9 , 25 ,
29 , 45 ]. However, the value of these radiopharmaceuticals for human use remains to
be determined. Detection of PS externalization can be a very good alternative method
for apoptosis detection purposes. Work is underway to develop an accurate method
to find correct PS aptamer sequences using nucleic acid oligos [ 47 ] which are less
toxic, easy to synthesize and offer a cheap alternative to more hazardous other can-
didates. The interested reader is encouraged to read recently published articles [ 5 ,
47 ] for details regarding the generation of aptamer-based probes for detecting and
for regulating apoptosis with potential relevance in cancer treatment. In this context
the early detection of response to therapy and the possibility to augment treatment
by the use of aptamers would have a huge clinical benefit. However, there are many
other potential benefits to be derived from a molecular imaging probe for apoptosis in