Proteasome inhibitors (PI), mainly targeting the β5 subunit of the
20S proteasome, are widely used in the treatment of
multiple myeloma (MM). However, PI resistance remains an unresolved problem in the
therapy of relapsed and refractory MM. To develop a new PI that targets other
proteasome subunits, we examined the anti-MM activity of a novel syringolin analog, syringolog-1, which inhibits the activity of both the β5 and β2 subunits. Syringolog-1 exhibited marked cytotoxicity against various MM cell lines and anti-
tumor activity towards
bortezomib (Btz)-resistant MM cells through the dual inhibition of
chymotrypsin-like (β5 subunit) and
trypsin-like (β2 subunit) activities. MM cells, including Btz-resistant cells, showed elevated CHOP and NOXA expression after syringolog-1 treatment, indicating the induction of excessive endoplasmic reticulum stress during syringolog-1 treatment. Similar activities of syringolog-1 were also observed in freshly prepared MM cells derived from patients. To clarify the anti-
tumor mechanism of dual inhibition of both the β5 and β2 subunits of the
proteasome, PSMB5 and PSMB7 were co-inhibited in MM cells. This resulted in increased apoptosis of MM cells accompanied by accumulation of
ubiquitinated proteins compared to inhibition of either PSMB7 or PSMB5 alone, indicating an enhanced effect by double inhibition of β2 and β5 activities. In conclusion, this syringolin analog, a dual inhibitor of
proteasome β2 and β5 activities, exhibited potent anti-
tumor effects on MM cells and may be useful for overcoming Btz-resistance in the treatment of MM.