Biomedical Engineering Reference
In-Depth Information
nonsmall-cell lung carcinoma, renal cell cancer, Lewis lung carcinoma, and pan-
creatic cancer [50-52
,
55
,
56].
As remarked previously, the efficacy of bortezomib is probably dependent on
other mechanisms in addition to NF-
κ
B inhibition. By directly comparing the effi-
B-kinase specific inhibitor PS-1145 in multiple
myeloma cells, it was found that bortezomib inhibited cell proliferation completely
in contrast to PS-1145, which inhibited only 20-50%, although both compounds
inhibited NF-
cacy of bortezomib and the I
κ
B activity completely [57]. Kenneth C. Anderson and colleagues
showed subsequently that in human multiple myeloma cells, bortezomib downreg-
ulates growth and survival pathways (e.g., IGF-1 receptor pathway; IGF-1 stimulates
Akt-signaling) and antiapoptotic genes, and upregulates proapoptotic genes, result-
ing in apoptosis [55
,
58
,
59]. The authors suggest that bortezomib-induced NF-
κ
B
inhibition causes a decrease in the antiapoptotic protein BcL-2 and the BcL-2 family
member A1/Bfl-1, leading to cytochrome C release and caspase-9 activation, in other
words, activation of the intrinsic apoptotic pathway. Furthermore, they suggest that
bortezomib causes p53-phosphorylation and subsequent jun N-terminal kinase
(JNK)-activation, leading to Fas upregulation. Additionally, an increase in c-myc
levels was observed, which correlated with an increase in FasL. The higher expres-
sion of both Fas and its ligand FasL would explain the observed activation of caspase-
8, which is the initiator caspase of the extrinsic apoptotic pathway. The killing signal
delivered by caspase-8 activation will be enhanced by the downregulation of NF-
κ
κ
B,
as NF-
B inhibition will lead to a decrease in FLICE inhibitory protein (FLIP)
levels, which is a physiological inhibitor of caspase-8 activation [60]. These obser-
vations show that inhibition of the proteasome in multiple myeloma cells leads to
the concurrent modulation of multiple transcription factors that, together, tip the
balance between life and death to the advantage of the latter. Presently, other
proteasome inhibitors (with distinct structural features) are under development. For
example, the lactacystin PS-519 has already entered clinical trials for treatment of
patients with poststroke and myocardial infarction reperfusion injuries [51
,
52].
κ
10.3.2
N
ONSTEROIDAL
A
NTIINFLAMMATORY
D
RUGS
At present, nonsteroidal antiinflammatory drugs (NSAIDs) are the most widely
prescribed antiinflammatory drugs. It was estimated that in the United States, five
to ten billion dollars are spent on NSAIDs, which are used in cardiovascular disease,
for relief of pain symptoms in minor injuries and headaches, and to alleviate dis-
comfort in serious inflammatory and joint diseases [61]. NSAIDs are known to
inhibit the activity of cyclooxygenases (COXs), which are involved in prostaglandin
(PG) synthesis [62
,
63]. As PGs play an important role in many processes other than
inflammation, such as blood clotting, ovulation, bone metabolism, nerve function,
wound healing, kidney function, and blood vessel tone, there is the accompanying
risk of cytotoxic side effects associated with the application of COX-inhibitors [61].
Aspirin inhibits the activity of the constitutively expressed COX-1 by acetylating it;
however, it has been shown that this is probably not the only mode of action of
NSAIDs [64]. A second mode of action of aspirin is that it prevents the phospho-
rylation of IKK
β
(and not IKK
α
) by binding to its adenosine triphosphate
