Fenretinide targets the side population in myeloma cell line NCI-H929 and potentiates the efficacy of antimyeloma with bortezomib and dexamethasone regimen
Fenretinide targets the side population in myeloma cell line NCI-H929 and potentiates the efficacy of antimyeloma with bortezomib and dexamethasone regimen
复制标题
Fenretinide 针对骨髓瘤细胞系 NCI-H929 中的侧群，并增强硼替佐米和地塞米松方案的抗骨髓瘤功效。
DOI：
10.1016/j.leukres.2016.10.010
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发表时间：
2016-12-01
影响因子：
2.7
通讯作者：
Hou, Jian
中科院分区：
文献类型：
--
作者：
Yan, Wenqing;Du, Juan;Hou, Jian
侧群(SP)细胞是一种富含肿瘤起始细胞的亚群，已被我们和其他先前的研究证实在多发性骨髓瘤(MM)中具有干细胞样特性。然而，缺乏针对肿瘤起始细胞的药物是MM治疗的一个挑战。此前，耐受性良好的维生素A衍生物芬维奈德已被证明对白血病干细胞起作用，但其对骨髓瘤干细胞的作用仍不清楚。本研究在Hoechst-33342染色的基础上，用流式细胞术分离NCI-H929细胞中的SP和非SP(MP)细胞，全面检测了非维甲酸对骨髓瘤干细胞特性的影响。我们发现，在生理浓度下，芬维甲素能够根除MM、SP和MP细胞，但不能根除正常骨髓单个核细胞(BMMC)。芬维奈德单独及与硼替佐米、地塞米松合用对MM SP细胞有选择性细胞毒作用。特别是SP细胞对非维甲酸高度敏感，并与硼替佐米和地塞米松联用进行集落形成和凋亡检测。因此，明显的非维甲酸诱导的细胞凋亡与ROS的快速产生有关。因此，我们认为非维甲酸是一种针对肿瘤起始细胞的有效药物，可能是治疗多发性骨髓瘤的一种有前途的治疗药物。(C)2016爱思唯尔有限公司。保留所有权利。
Side population (SP) cells, a subset of enriched tumor initiating cells, have been demonstrated to have stem cell-like properties in multiple myeloma (MM) by us as well as other previous studies. A lack of agents targeting tumor initiating cells, however, represents a challenge in the treatment of MM. Previously, fenretinide, a well-tolerated vitamin A derivative, has been shown to exert effect on leukemic stem cells, but its actions against myeloma stem-like cells are still unknown. In this study, the effects of fenretinide on myeloma stem-like cells characteristic was comprehensively examined in SP and non-SP (MP) cells of NCI-H929 cell sorted by flow cytometry-based on Hoechst 33342 stain. We find that fenretinide is capable of eradicating MM SP and MP cells, but not normal bone marrow mononuclear cells (BMMCs) at physiologically achievable concentrations. Fenretinide alone exerted a selective cytotoxic effect on MM SP cells, as well as in combination with bortezomib and dexamethasone. In particular, SP cells were highly sensitive to fenretinide, and in combination with bortezomib and dexamethasone in colony formation and apoptosis assays. Accordingly, the apparent fenretinide-induced-apoptosis was linked to the rapid generation of reactive oxygen species (ROS). Therefore, we propose that fenretinide is a potent agent that targets tumor initiating cells and may be a promising therapeutic agent in MM treatment. (C) 2016 Elsevier Ltd. All rights reserved.