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RKIP would influence and modulate the phenotypic outcome of more than one mode
of function and provide an additively substantive result.
Inhibition of the NF-κB survival signalling seems to upregulate RKIP. Anti-CD20
antibodies upregulate RKIP expression in this way (Jazirehi et al., 2005; Vega et al.,
2009). The mechanism of the upregulation is unclear, but inhibition of NF-κB path-
way occurs together with the downregulation of the anti-apoptotic Bcl-x(L) and
Bfl-1/A1, a homologue of Bcl-2. As noted above, NO also inhibits NF-κB pathway
and induces RKIP expression.
Proteasome Inhibitors
The proteasome consists of a cylindrical core particle with two identical regulatory
particles one at each end of the cylindrical core. Some subunits of the regulatory
particles can recognise ubiquitin. Ubiquitinated proteins bind to the regulatory par-
ticles. The ATPase components unfold the protein which then moves to the central
core where it is degraded. Proteasome inhibition has been recognised for some time
as valid approach in cancer treatment. Many inhibitors have attracted much attention
since the successful introduction of Bortezomib in the treatment of multiple mye-
loma and mantle cell lymphoma and evaluated in many other forms of cancer, for
example NSCLC, prostate cancer and B-cell neoplasms, follicular Non-Hodgkin's
lymphoma, Waldenstrom's macroglobulinemia, chronic and acute lymphocytic leu-
kaemia, gliomas and colorectal and pancreatic cancers. Bortezomib also counteracts
chemoresistance and induces cell cycle arrest and apoptosis.
NPI-0052 (salinosporamide A; marizomib) is another inhibitor on which much
attention has been focused. It binds irreversibly to inhibit proteasome action.
Carfilzomib is also a proteasome inhibitor that is undergoing comparative evalu-
ation for efficacy with Bortezomib. Omuralide is another inhibitor structurally
related to NPI-0052. NPI-0052 and Bortezomib in combination induce apoptosis
in several ways including caspase activation, PARP and inhibition of NF-κB sig-
nalling (Chauhan et al., 2008; Rocaro et al., 2008). Rocaro et al. (2008) also impli-
cated inhibition of Akt pathway and noted abrogation of Akt signalling reduced the
cytotoxic effects of NPI-0052. However, Sloss et al. (2008) found that NPI-0052
and Bortezomib indeed activated EGFR, ERK and inhibition of these enhanced the
antitumour effects exerted by NPI-0052 and Bortezomib. NPI-0052 and Bortezomib
treatment inhibited cell adhesion and migration. This could be accounted for by the
inhibition of Snail and consequent upregulation of E-cadherin and of RKIP (Baritaki
et al., 2009).
Four clinical trials are listed in clinicaltrials.gov/ct2/results?term=NPI-0052+.
A phase I clinical trial to evaluate the safety and efficacy of NPI-0052 is under
way in multiple myeloma (NCT00461045) and another non-randomised study
into its efficacy, pharmacokinetics and pharmaodynamics in combination with the
HDAC inhibitor Vorinostat in NSCLC, melanoma, lymphoma and pancreatic can-
cer (NCT00667082). Phase I trials in advanced malignancies (NCT00629473) and
refractory lymphomas (NCT00396864) are in progress. No information about the
outcome is available at present.
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