Development lines and patient-derived cells by suppressing

Development of
orally bioavailable second-generation proteasome inhibitors MLN9708 (Ixazomib, Ninlaro®) and CEP-18770
showed proteasome-inhibitory action equivalent to bortezomib but with better
pharmacokinetic properties. Ixazomib (Ninlaro®) is the first orally
administered proteasome inhibitor approved by FDA is currently being used in
the US, Europe and Japan in combination with lenalidomide and dexamethasone in patients with relapsed and/or
refractory myeloma (Manasanch, and Orlowski, 2017; Al-Salama et al.,
2017). Treatment with
MLN9708 or its biologically active form MLN2238 (ixazomib citrate, Millennium
Pharmaceuticals, Inc.) predominantly inhibits growth and
triggers apoptosis in multiple myeloma cells that were already impervious to traditional
and bortezomib therapies without influencing regular cells (Chauhan
et al., 2011). Although CEP-18770 (delanzomib)
showed promising results in promoting apoptosis in human
multiple myeloma cell lines and patient-derived cells by suppressing NF-pr–mediated signaling
pathways and by inhibiting endothelial cell
survival, and RANKL-induced osteoclastogenesis in vitro (Piva et al., 2008), development of delanzomib
for myeloma was discontinued owing to its dose-limiting toxicities (Vogl et
al., 2017). Another proteasome
inhibitor, PR-957 prevents experimental autoimmune disease rheumatoid arthritis
in the mouse model by acting directly on the low-molecular-mass polypeptide-7 (LMP7), which is the chymotrypsin-like subunit of the
immunoproteasome (Popovic et al., 2014).

Efficacy of other proteasome inhibitors, including the irreversible epoxyketone Oprozomib
(Shah et al., 2015), and the intravenous marine-derived ?-lactone-?-lactam Marizomib (NPI-0052; salinosporamide A) (Potts et al., 2011) has been evaluated clinically
either as single agent or in combination with other drugs (Manasanch, and
Orlowski, 2017). Marizomib showed
broader and irreversible inhibition of all three 20S proteasome proteolytic activities in various in vitro models, and is efficacious in vivo against multiple myeloma, other hematologic malignancies,
and solid tumor models, including colon and pancreatic carcinomas (Potts et al., 2011). Mechanistically, first and second generation
proteasome inhibitors triggers apoptosis in cultured cell lines and murine models of
cancer that is associated with enhanced expression
of proapoptotic genes like p53,
p21, Noxa, Puma, and E2F, downregulation of antiapoptotic genes, activation
of caspases cascade and the inhibition of NF-?B signalling by blocking
degradation of the NF-?B inhibitor I?B.

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