Authors' Affiliations: Centro de Investigación del Cáncer, IBMCC (Universidad de Salamanca-CSIC); Centro en Red de Medicina Regenerativa y Terapia Celular de Castilla y León; Hospital Universitario de Salamanca-IBSAL, Salamanca; Laboratorio de Imagen del Cáncer, Centro de Investigación Médica Aplicada, Universidad de Navarra, Pamplona, Spain; MGH Cancer Center, Massachusetts General Hospital; Dana-Farber Cancer Institute, Harvard Medical School, Boston; Millennium Pharmaceuticals, Inc., Cambridge, Massachusetts, USA; and Departments of Cell Biology and Immunology, University Medical Center Utrecht, Utrecht, The Netherlands.
Clin Cancer Res. 2014 Mar 15;20(6):1542-54. doi: 10.1158/1078-0432.CCR-13-1657. Epub 2014 Jan 31.
MLN9708 (ixazomib citrate), which hydrolyzes to pharmacologically active MLN2238 (ixazomib), is a next-generation proteasome inhibitor with demonstrated preclinical and clinical antimyeloma activity, but yet with an unknown effect on myeloma bone disease. Here, we investigated its bone anabolic and antiresorptive effects in the myeloma setting and in comparison with bortezomib in preclinical models.
The in vitro effect of MLN2238 was tested on osteoclasts and osteoclast precursors from healthy donors and patients with myeloma, and on osteoprogenitors derived from bone marrow mesenchymal stem cells also from both origins. We used an in vivo model of bone marrow-disseminated human myeloma to evaluate MLN2238 antimyeloma and bone activities.
Clinically achievable concentrations of MLN2238 markedly inhibited in vitro osteoclastogenesis and osteoclast resorption; these effects involved blockade of RANKL (receptor activator of NF-κB ligand)-induced NF-κB activation, F-actin ring disruption, and diminished expression of αVβ3 integrin. A similar range of MLN2238 concentrations promoted in vitro osteoblastogenesis and osteoblast activity (even in osteoprogenitors from patients with myeloma), partly mediated by activation of TCF/β-catenin signaling and upregulation of the IRE1 component of the unfolded protein response. In a mouse model of bone marrow-disseminated human multiple myeloma, orally administered MLN2238 was equally effective as bortezomib to control tumor burden and also provided a marked benefit in associated bone disease (sustained by both bone anabolic and anticatabolic activities).
Given favorable data on pharmacologic properties and emerging clinical safety profile of MLN9708, it is conceivable that this proteasome inhibitor may achieve bone beneficial effects in addition to its antimyeloma activity in patients with myeloma.
MLN9708（柠檬酸伊沙佐米）可水解为具有临床前和临床抗骨髓瘤活性的 MLN2238（伊沙佐米），是一种新一代蛋白酶体抑制剂，但对骨髓瘤骨病的影响尚不清楚。在这里，我们研究了它在骨髓瘤环境中的骨合成代谢和抗吸收作用，并与临床前模型中的硼替佐米进行了比较。
在体外，测试了 MLN2238 对来自健康供体和骨髓瘤患者的破骨细胞和破骨细胞前体以及来自骨髓间充质干细胞的成骨细胞的影响。我们使用骨髓播散性人骨髓瘤的体内模型来评估 MLN2238 的抗骨髓瘤和骨活性。
临床可达到的 MLN2238 浓度显著抑制体外破骨细胞生成和破骨细胞吸收；这些作用涉及阻断 RANKL（核因子-κB 配体受体激活剂）诱导的 NF-κB 激活、F-肌动蛋白环破坏和减少 αVβ3 整合素表达。类似范围的 MLN2238 浓度促进体外成骨细胞生成和成骨细胞活性（甚至在来自骨髓瘤患者的成骨细胞前体中），部分由 TCF/β-连环蛋白信号激活和未折叠蛋白反应的 IRE1 成分上调介导。在骨髓播散性人多发性骨髓瘤的小鼠模型中，口服给予 MLN2238 与硼替佐米一样有效控制肿瘤负担，并且对相关骨病也有明显益处（由骨合成代谢和抗吸收活性共同维持）。
鉴于 MLN9708 在药理学特性和新兴临床安全性方面的有利数据，可以想象这种蛋白酶体抑制剂除了在骨髓瘤患者中具有抗骨髓瘤活性外，还可能具有骨有益作用。
