Identification of an ABCB1 (P-glycoprotein)-positive carfilzomib-resistant myeloma subpopulation by the pluripotent stem cell fluorescent dye CDy1.
Identification of an ABCB1 (P-glycoprotein)-positive carfilzomib-resistant myeloma subpopulation by the pluripotent stem cell fluorescent dye CDy1.
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DOI：
10.1002/ajh.23387
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发表时间：
2013-04
影响因子：
12.8
通讯作者：
Hawley, Robert G.
中科院分区：
文献类型：
--
作者：
Hawley, Teresa S.;Riz, Irene;Yang, Wenjing;Wakabayashi, Yoshiyuki;DePalma, Louis;Chang, Young-Tae;Peng, Weiqun;Zhu, Jun;Hawley, Robert G.
多发性骨髓瘤（MM）的特征是分化浆细胞的恶性扩张。尽管许多化疗药物对MM细胞表现出细胞毒活性，但由于肿瘤细胞对抗癌药物产生抗药性，患者不可避免地会死于疾病。癌症干细胞假说假设一小部分化疗耐药的癌细胞亚群负责肿瘤的增殖。在此，我们报告多能干细胞染料 CDy1 的流出识别了 MM 细胞系中的一个亚群，其特征是 P-糖蛋白表达增加，P-糖蛋白是由 ABCB1 编码的 ABC（ATP 结合盒）转运蛋白超家族的成员。我们还证明，ABCB1 过度表达的 MM 细胞对第二代蛋白酶体抑制剂卡非佐米具有耐药性，该抑制剂最近获得美国食品和药物管理局加速批准用于治疗屈光性 MM。此外，药物选择后敏感MM细胞对卡非佐米的耐药性增加与ABCB1细胞表面表达的上调相关，而ABCB1细胞表面表达的上调与通过CDy1流出测量的转运蛋白活性增加相关。我们进一步表明，通过与目前正在进行MM临床试验的hedgehog通路拮抗剂vismodegib共同治疗，可以在体外实现MM细胞对卡非佐米的化学增敏。因此，CDy1 外流可能是一种有用的检测方法，可用于确定 ABCB1 的高表达是否预示着接受卡非佐米治疗的 MM 患者临床反应不佳。我们的数据还表明，包含 vismodegib 可能是逆转 ABCB1 介导的耐药性（如果发生）的潜在策略。
Multiple myeloma (MM) is characterized by the malignant expansion of differentiated plasma cells. Although many chemotherapeutic agents display cytotoxic activity toward MM cells, patients inevitably succumb to their disease because the tumor cells become resistant to the anticancer drugs. The cancer stem cell hypothesis postulates that a small subpopulation of chemotherapy-resistant cancer cells is responsible for propagation of the tumor. Herein we report that efflux of the pluripotent stem cell dye CDy1 identifies a subpopulation in MM cell lines characterized by increased expression of P-glycoprotein, a member of the ABC (ATP-binding cassette) superfamily of transporters encoded by ABCB1. We also demonstrate that ABCB1-overexpressing MM cells are resistant to the second-generation proteasome inhibitor carfilzomib that recently received accelerated approval for the treatment of therapy-refractive MM by the U.S. Food and Drug Administration. Moreover, increased resistance to carfilzomib in sensitive MM cells following drug selection was associated with upregulation of ABCB1 cell-surface expression which correlated with increased transporter activity as measured by CDy1 efflux. We further show that chemosensitization of MM cells to carfilzomib could be achieved in vitro by cotreatment with vismodegib, a hedgehog pathway antagonist which is currently in MM clinical trials. CDy1 efflux may therefore be a useful assay to determine whether high expression of ABCB1 is predictive of poor clinical responses in MM patients treated with carfilzomib. Our data also suggest that inclusion of vismodegib might be a potential strategy to reverse ABCB1-mediated drug resistance should it occur.
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