Potent anti-tumor activity of a syringolin analog in multiple myeloma: a dual inhibitor of proteasome activity targeting β2 and β5 subunits

Abstract

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.

Geranylgeranyl diphosphate synthase inhibitor and proteasome inhibitor combination therapy in multiple myeloma

“…In another study, a specific inhibitor of the proteasome β2 subunit activated the UPR and induced cytotoxicity in bortezomib-resistant MM cells when combined with either bortezomib or carfilzomib [ 29 ]. Dual inhibition of the β2 and β5 subunits using a PI termed syringolog-1 resulted in increased expression of CHOP, ATF3, and XBP1, as well as induction of apoptosis in both bortezomib resistant and sensitive cell lines [ 30 ]. Likewise, we observed upregulation of several UPR mediators upon bortezomib or carfilzomib treatment, including ATF4, IRE1, and p-eIF2a.…”

Proteasome Inhibition in Multiple Myeloma: Head-to-Head Comparison of Currently Available Proteasome Inhibitors

“…Inhibition of ABCB-type transporters is able to sensitize the CFZ-resistant cells to b5/b2 inhibition and likewise to CFZ (Besse et al, 2018;Abt et al, 2018;Soriano et al, 2016). Several reports showed effective b5/b2 proteasome inhibition by two independent drugs, or by one single molecule, such as CFZ or syringolin analog syringolog-1 (Kraus et al, 2015;Weyburne et al, 2017;Yoshida et al, 2018). We here show that b5/b2 dual inhibition using two selective inhibitors is more effective than one bispecific inhibitor, as lower doses of b2 inhibitor are needed to fully inhibit b2 activity when the b5 site is inactive, compared with the setting when b5 is active.…”

The Landscape of Signaling Pathways and Proteasome Inhibitors Combinations in Multiple Myeloma

“…Even though all PIs available for therapy are designed to target the β5 subunit of the proteasome, several authors have demonstrated that the simultaneous inhibition of β5 and β2 either by combinatorial therapy (bortezomib/carfilzomib and LU-102) or dual inhibition (syringolin analog) can improve the cytotoxic effects of proteasome inhibition [ 106 , 172 ]. Interestingly, the dual inhibitor was able to overcome bortezomib resistance, while the combination of two inhibitors failed to re-sensitize cells.…”