Aminopeptidase inhibition as a targeted treatment strategy in myeloma
Aminopeptidase inhibition as a targeted treatment strategy in myeloma
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DOI：
10.1158/1535-7163.mct-08-0735
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发表时间：
2009-04-01
影响因子：
5.7
通讯作者：
Davies, Faith E.
中科院分区：
文献类型：
--
作者：
Moore, Hannah E.;Davenport, Emma L.;Davies, Faith E.
骨髓瘤细胞高度依赖于未折叠的蛋白质反应来正确组装折叠的免疫球蛋白。因此，通过抑制氨肽酶酶系统（其催化来自蛋白质NH 2末端的氨基酸水解）来靶向骨髓瘤细胞内的蛋白质处理代表了一种治疗方法。新型氨肽酶抑制剂--氨肽酶-2797能够抑制骨髓瘤细胞的增殖并诱导其生长停滞和凋亡，包括对常规化疗药物耐药的细胞。它对骨髓基质细胞（BMSC）增殖的抑制作用最小，但能够克服微环境保护作用，抑制骨髓瘤细胞与BMSC结合的增殖，以及骨髓瘤细胞和BMSC结合在一起时观察到的血管内皮生长因子水平的增加。硼替佐米、美法仑和地塞米松具有相加和协同作用。细胞凋亡通过半胱天冬酶依赖性和非半胱天冬酶依赖性途径发生，其中Noxa增加，Mcl-1裂解和未折叠蛋白反应活化。也可以看到自噬。CYP-2797引起参与蛋白酶体/泛素途径的基因以及氨基肽酶和氨基酸剥夺反应基因的上调。总之，使用氨肽酶抑制剂抑制蛋白质周转导致骨髓瘤细胞凋亡，代表了一种新的治疗方法，值得在临床环境中进一步研究。[Mol癌症治疗2009;8（4）：762-70]
Myeloma cells are highly dependent on the unfolded protein response to assemble folded immunoglobulins correctly. Therefore, targeting protein handling within a myeloma cell by inhibiting the aminopeptidase enzyme system, which catalyses the hydrolysis of amino acids from the proteins NH2 terminus, represents a therapeutic approach. CHR-2797, a novel aminopeptidase inhibitor, is able to inhibit proliferation and induce growth arrest and apoptosis in myeloma cells, including cells resistant to conventional chemotherapeutics. It causes minimal inhibition of bone marrow stromal cell (BMSC) proliferation but is able to overcome the microenvironmental protective effects, inhibiting the proliferation of myeloma cells bound to BMSCs and the increase in vascular endothelial growth factor levels seen when myeloma cells and BMSCs are bound together. Additive and synergistic effects are seen with bortezomib, melphalan, and dexamethasone. Apoptosis occurs via both caspase-dependent and non-caspase-dependent pathways with an increase in Noxa, cleavage of Mcl-1, and activation of the unfolded protein response. Autophagy is also seen. CHR-2797 causes an up-regulation of genes involved in the proteasome/ubiquitin pathway, as well as aminopeptidases, and amino acid deprivation response genes. In conclusion, inhibiting protein turnover using the aminopeptidase inhibitor CHR-2797 results in myeloma cell apoptosis and represents a novel therapeutic approach that warrants further investigation in the clinical setting. [Mol Cancer Ther 2009;8(4):762-70]