Thiasyrbactins Induce Cell Death via Proteasome Inhibition in Multiple Myeloma Cells

Abstract

Background/aim: Proteasome inhibition is a validated therapeutic strategy for the treatment of refractory and relapsed multiple myeloma (MM) and mantle cell lymphoma. We previously showed that thiasyrbactins (NAM compounds) are inhibitors with an affinity for the trypsin-like (T-L, β2) site of the constitutive proteasome, and more profoundly for the T-L site of the immunoproteasome.

Materials and methods: In this study, the biological activity of three NAM compounds was evaluated using four MM cell lines (ARD, U266, MM1R, and MM1S). We assessed the effect of (NAM-93, NAM-95, and NAM-105 on cell viability, as well as cell-based proteasomal activities, and determined the EC₅₀ and Ki₅₀ values, respectively.

Results: MM cells were most sensitive to NAM-93 with EC₅₀ values <0.75 μM after 48 h of treatment. NAM-105 had a similar profile in most of the MM cells with EC₅₀ values ranging between 0.42 and 3.02 μM. The level of inhibition of the proteasome T-L sub-catalytic activity in actively-growing MM cells was similar for NAM-93 and NAM-105. However, in each cell line, NAM-93 was more effective than NAM-105 at inhibiting overall trypsin-like sub-catalytic activity while NAM-105 was typically more effective at inhibiting overall chymotrypsin-like (CT-L, β5) sub-catalytic activity.

Conclusion: These results show for the first time the proteasome-targeted biological activity of thiasyrbactins in MM tumor cells.

Keywords: NAM; Proteasome inhibitors; caspase-like; chymotrypsin-like activity; immunoproteasome; multiple myeloma; thiasyrbactin; trypsin-like.