Rational combination treatment with histone deacetylase inhibitors and immunomodulatory drugs in multiple myeloma.
Rational combination treatment with histone deacetylase inhibitors and immunomodulatory drugs in multiple myeloma.
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DOI：
10.1038/bcj.2015.38
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发表时间：
2015-05-15
影响因子：
12.8
通讯作者：
Anderson KC
中科院分区：
文献类型：
--
作者：
Hideshima T;Cottini F;Ohguchi H;Jakubikova J;Gorgun G;Mimura N;Tai YT;Munshi NC;Richardson PG;Anderson KC
免疫调节药物（IMiD）沙利度胺、来那度胺（Len）和泊马度胺通过靶向cereblon从而影响IZF 1/3、c-Myc和IRF 4来触发多发性骨髓瘤（MM）的抗肿瘤活性。组蛋白去乙酰化酶抑制剂（HDACi）也下调c-Myc。因此，我们确定IMiD与HDACi是否通过抑制或下调c-Myc触发显著的MM细胞生长抑制。Len与非选择性HDACi辛二酰苯胺异羟肟酸或I类HDAC选择性抑制剂MS 275的组合治疗诱导协同细胞毒性，与c-Myc的下调相关。出乎意料的是，我们观察到这些药物触发了Cereblon（CRBN）（IMiD的主要靶蛋白）水平的降低。事实上，用MS 275随后用Len顺序处理MM细胞显示出比用该组合同时处理更低的功效。重要的是，ACY 1215，一种对I类HDAC具有最小影响的HDAC 6抑制剂，与Len一起诱导协同MM细胞毒性而不改变CRBN表达。我们的结果表明，仅适度的I类HDAC抑制能够与Len组合诱导协同MM细胞毒性。这些研究可以提供利用HDACi与Len组合以避免CRBN下调和增强抗MM活性的框架。
Immunomodulatory drugs (IMiDs) thalidomide, lenalidomide (Len) and pomalidomide trigger anti-tumor activities in multiple myeloma (MM) by targetting cereblon and thereby impacting IZF1/3, c-Myc and IRF4. Histone deacetylase inhibitors (HDACi) also downregulate c-Myc. We therefore determined whether IMiDs with HDACi trigger significant MM cell growth inhibition by inhibiting or downregulating c-Myc. Combination treatment of Len with non-selective HDACi suberoylanilide hydroxamic acid or class-I HDAC-selective inhibitor MS275 induces synergic cytotoxicity, associated with downregulation of c-Myc. Unexpectedly, we observed that decreased levels of cereblon (CRBN), a primary target protein of IMiDs, was triggered by these agents. Indeed, sequential treatment of MM cells with MS275 followed by Len shows less efficacy than simultaneous treatment with this combination. Importantly ACY1215, an HDAC6 inhibitor with minimal effects on class-I HDACs, together with Len induces synergistic MM cytotoxicity without alteration of CRBN expression. Our results showed that only modest class-I HDAC inhibition is able to induce synergistic MM cytotoxicity in combination with Len. These studies may provide the framework for utilizing HDACi in combination with Len to both avoid CRBN downregulation and enhance anti-MM activities.
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影响因子：
14.8
作者：
Bradner, James E.;West, Nathan;Grachan, Melissa L.;Greenberg, Edward F.;Haggarty, Stephen J.;Warnow, Tandy;Mazitschek, Ralph
通讯作者：
Mazitschek, Ralph
影响因子：
2.7
作者：
Cheng, Yun-Chih;Lin, Hsiupen;Liu, H. Eugene
通讯作者：
Liu, H. Eugene
影响因子：
20.3
作者：
Catley, Laurence;Weisberg, Ellen;Anderson, Kenneth C.
通讯作者：
Anderson, Kenneth C.
影响因子：
11.4
作者：
Lopez-Girona, A.;Mendy, D.;Ito, T.;Miller, K.;Gandhi, A. K.;Kang, J.;Karasawa, S.;Carmel, G.;Jackson, P.;Abbasian, M.;Mahmoudi, A.;Cathers, B.;Rychak, E.;Gaidarova, S.;Chen, R.;Schafer, P. H.;Handa, H.;Daniel, T. O.;Evans, J. F.;Chopra, R.
通讯作者：
Chopra, R.
影响因子：
56.9
作者：
Ito, Takumi;Ando, Hideki;Handa, Hiroshi
通讯作者：
Handa, Hiroshi