文章：

组蛋白去乙酰化酶抑制剂与免疫调节药物在多发性骨髓瘤中的合理联合治疗

Rational combination treatment with histone deacetylase inhibitors and immunomodulatory drugs in multiple myeloma

原文发布日期：2015-05-15

DOI: 10.1038/bcj.2015.38

类型: Original Article

开放获取: 是

英文摘要：

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.

摘要翻译： 

免疫调节药物（IMiDs）沙利度胺、来那度胺（Len）和泊马度胺通过靶向cereblon蛋白，进而影响IZF1/3、c-Myc及IRF4，从而在多发性骨髓瘤（MM）中发挥抗肿瘤活性。组蛋白去乙酰化酶抑制剂（HDACi）同样能下调c-Myc表达。因此，我们探究了IMiDs与HDACi联用是否通过抑制或下调c-Myc来显著阻断MM细胞生长。来那度胺与非选择性HDACi伏立诺他或I类HDAC选择性抑制剂MS275的联合治疗可产生协同细胞毒性，该效应与c-Myc下调相关。出乎意料的是，我们发现这些药物会引发IMiDs主要靶蛋白cereblon（CRBN）水平的降低。事实上，先用MS275预处理MM细胞再用来那度胺的序贯治疗，其疗效低于两药同时联合使用。重要的是，主要作用于HDAC6而对I类HDAC影响甚微的抑制剂ACY1215，与来那度胺联用可在不改变CRBN表达的情况下诱导协同MM细胞毒性。我们的研究结果表明，仅需适度抑制I类HDAC即可与来那度胺产生协同抗MM细胞毒性。这些研究可能为HDACi与来那度胺联合应用的临床方案提供理论依据，既可避免CRBN下调，又能增强抗MM活性。

原文链接：

Rational combination treatment with histone deacetylase inhibitors and immunomodulatory drugs in multiple myeloma