Clinical and Experimental Oncology Department, Universidade Federal de Sao Paulo, Sao Paulo, UNIFESP, Brazil.
Curr Mol Med. 2019;19(2):112-119. doi: 10.2174/1566524019666190305134441.
Multiple myeloma (MM) cells accumulate in the bone marrow and produce enormous quantities of immunoglobulins, causing endoplasmatic reticulum stress and activation of protein handling machinery, such as heat shock protein response, autophagy and unfolded protein response (UPR).
We evaluated cell lines viability after treatment with bortezomib (B) in combination with HSP70 (VER-15508) and autophagy (SBI-0206965) or UPR (STF- 083010) inhibitors.
For RPMI-8226, after 72 hours of treatment with B+VER+STF or B+VER+SBI, we observed 15% of viable cells, but treatment with B alone was better (90% of cell death). For U266, treatment with B+VER+STF or with B+VER+SBI for 72 hours resulted in 20% of cell viability and both treatments were better than treatment with B alone (40% of cell death). After both triplet combinations, RPMI-8226 and U266 presented the overexpression of XBP-1 UPR protein, suggesting that it is acting as a compensatory mechanism, in an attempt of the cell to handle the otherwise lethal large amount of immunoglobulin overload.
Our in vitro results provide additional evidence that combinations of protein homeostasis inhibitors might be explored as treatment options for MM.
多发性骨髓瘤（MM）细胞在骨髓中积累并产生大量免疫球蛋白，导致内质网应激和蛋白质处理机制的激活，如热休克蛋白反应、自噬和未折叠蛋白反应（UPR）。
我们评估了细胞系在用硼替佐米（B）联合 HSP70（VER-15508）、自噬（SBI-0206965）或 UPR（STF-083010）抑制剂处理后的存活率。
对于 RPMI-8226，在用 B+VER+STF 或 B+VER+SBI 处理 72 小时后，我们观察到 15%的存活细胞，但单独用 B 处理效果更好（90%的细胞死亡）。对于 U266，用 B+VER+STF 或 B+VER+SBI 处理 72 小时后，有 20%的细胞存活，这两种处理都优于单独用 B 处理（40%的细胞死亡）。在这两种三联组合后，RPMI-8226 和 U266 均表现出 UPR 蛋白 XBP-1 的过表达，表明其作为一种代偿机制发挥作用，试图减轻大量免疫球蛋白过载对细胞的致命影响。
我们的体外结果提供了额外的证据，表明蛋白质稳态抑制剂的组合可能被探索作为 MM 的治疗选择。
