CRM1 Inhibition Sensitizes Drug Resistant Human Myeloma Cells to Topoisomerase II and Proteasome Inhibitors both In Vitro and Ex Vivo.
CRM1 Inhibition Sensitizes Drug Resistant Human Myeloma Cells to Topoisomerase II and Proteasome Inhibitors both In Vitro and Ex Vivo.
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DOI：
10.7150/jca.7080
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发表时间：
2013
影响因子：
3.9
通讯作者：
Sullivan DM
中科院分区：
文献类型：
--
作者：
Turner JG;Dawson J;Emmons MF;Cubitt CL;Kauffman M;Shacham S;Hazlehurst LA;Sullivan DM
多发性骨髓瘤（MM）仍然是一种无法治愈的疾病，尽管治疗方法有所改进，包括来那度胺/泊马度胺和硼替佐米/卡非佐米治疗以及高剂量化疗和自体干细胞挽救。需要新的药物靶点来进一步改善治疗结果。大分子的核输出在许多癌症中被错误调节，包括在血液恶性肿瘤如MM中。CRM 1（染色体维持蛋白-1）是一种普遍存在的蛋白质，其将大蛋白质（>40 kDa）从细胞核输出到细胞质。我们发现，小分子选择性核输出抑制剂（SINE）阻止CRM 1介导的p53和拓扑异构酶IIα（topo IIα）的输出。SINE的CRM 1抑制活性通过MM细胞中CRM 1货物p53和topo IIα的核质分离和免疫细胞化学染色来验证。我们发现，SINE分子降低细胞活力和诱导细胞凋亡时，无论是作为单一的药物在亚微摩尔范围内，当与多柔比星，硼替佐米，或卡非佐米，但不来那度胺，美法仑，或地塞米松组合。此外，CRM 1抑制使MM细胞系和患者骨髓瘤细胞对多柔比星、硼替佐米和卡非佐米敏感，但不影响外周血单核细胞或非骨髓瘤骨髓单核细胞，如细胞活力和凋亡测定所示。骨髓瘤细胞与骨髓基质细胞共培养诱导的耐药性可通过添加SINE分子来避免。这些结果支持继续开发SINE治疗MM患者。
Multiple myeloma (MM) remains an incurable disease despite improved treatments, including lenalidomide/pomalidomide and bortezomib/carfilzomib based therapies and high-dose chemotherapy with autologous stem cell rescue. New drug targets are needed to further improve treatment outcomes. Nuclear export of macromolecules is misregulated in many cancers, including in hematological malignancies such as MM. CRM1 (chromosome maintenance protein-1) is a ubiquitous protein that exports large proteins (>40 kDa) from the nucleus to the cytoplasm. We found that small-molecule Selective Inhibitors of Nuclear Export (SINE) prevent CRM1-mediated export of p53 and topoisomerase IIα (topo IIα). SINE's CRM1-inhibiting activity was verified by nuclear-cytoplasmic fractionation and immunocytochemical staining of the CRM1 cargoes p53 and topo IIα in MM cells. We found that SINE molecules reduced cell viability and induced apoptosis when used as both single agents in the sub-micromolar range and when combined with doxorubicin, bortezomib, or carfilzomib but not lenalidomide, melphalan, or dexamethasone. In addition, CRM1 inhibition sensitized MM cell lines and patient myeloma cells to doxorubicin, bortezomib, and carfilzomib but did not affect peripheral blood mononuclear or non-myeloma bone marrow mononuclear cells as shown by cell viability and apoptosis assay. Drug resistance induced by co-culture of myeloma cells with bone marrow stroma cells was circumvented by the addition of SINE molecules. These results support the continued development of SINE for patients with MM.
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影响因子：
11.4
作者：
Etchin, J.;Sun, Q.;Kentsis, A.;Farmer, A.;Zhang, Z. C.;Sanda, T.;Mansour, M. R.;Barcelo, C.;McCauley, D.;Kauffman, M.;Shacham, S.;Christie, A. L.;Kung, A. L.;Rodig, S. J.;Chook, Y. M.;Look, A. T.
通讯作者：
Look, A. T.
影响因子：
5
作者：
Burzlaff, A;Kalesse, M;Scheper, T
通讯作者：
Scheper, T
影响因子：
3.7
作者：
Engel, R;Valkov, NI;Sullivan, DM
通讯作者：
Sullivan, DM
影响因子：
5.7
作者：
Nair RR;Emmons MF;Cress AE;Argilagos RF;Lam K;Kerr WT;Wang HG;Dalton WS;Hazlehurst LA
通讯作者：
Hazlehurst LA
影响因子：
20.3
作者：
ROECKLEIN, BA;TOROKSTORB, B
通讯作者：
TOROKSTORB, B