A novel hypoxia-selective epigenetic agent RRx-001 triggers apoptosis and overcomes drug resistance in multiple myeloma cells.
A novel hypoxia-selective epigenetic agent RRx-001 triggers apoptosis and overcomes drug resistance in multiple myeloma cells.
复制标题
一种新型的缺氧选择性表观遗传剂RRX-001触发凋亡并克服了多发性骨髓瘤细胞中的耐药性。
DOI：
10.1038/leu.2016.96
复制
发表时间：
2016-11
期刊：
影响因子：
11.4
通讯作者：
Anderson KC
中科院分区：
文献类型：
--
作者：
Das DS;Ray A;Das A;Song Y;Tian Z;Oronsky B;Richardson P;Scicinski J;Chauhan D;Anderson KC
低氧骨髓（BM）微环境赋予多发性骨髓瘤（MM）细胞生长/存活和耐药性。靶向MM细胞在其缺氧BM环境中的新疗法可以克服耐药性。最近的研究导致开发了一种具有低氧选择性表观遗传和一氧化氮供体特性的新型分子RRx-001。在这里，我们证明了RRx-001降低了MM细胞系和原代患者细胞的活力，并克服了耐药性。RRx-001在BM基质细胞存在下抑制MM细胞生长。RRx-001诱导的细胞凋亡与：1）半胱天冬酶的激活; 2）ROS和氮物质的释放; 3）通过ATM/γ-H2 AX诱导DNA损伤;和4）DNA甲基转移酶（DNMT）和整体甲基化的降低相关。RNA干扰研究显示，与DNMT 3a或DNMT 3b相比，DNMT 1在MM细胞存活中起主导作用。去泛素化酶USP 7刺激DNMT 1活性;相反，USP 7-siRNA降低DNMT 1活性并降低MM细胞活力。RRx-001加USP 7抑制剂P5091引发协同抗MM活性。MM异种移植研究表明，RRx-001耐受性良好，抑制肿瘤生长，并提高存活率。将RRx-001与泊马度胺、硼替佐米或SAHA组合诱导协同抗MM活性。我们的研究结果为将RRx-001（单独或联合）转化为MM的临床评价提供了依据。
The hypoxic bone-marrow (BM) microenvironment confers growth/survival and drug-resistance in multiple myeloma (MM) cells. Novel therapies targeting the MM cell in its hypoxic-BM milieu may overcome drug resistance. Recent studies led to the development of a novel molecule RRx-001 with hypoxia-selective epigenetic and Nitric Oxide-donating properties. Here we demonstrate that RRx-001 decreases the viability of MM cell lines and primary patient cells, as well as overcomes drug-resistance. RRx-001 inhibits MM cell growth in the presence of BM stromal cells. RRx-001 induced apoptosis is associated with: 1) activation of caspases; 2) release of ROS and nitrogen-species; 3) induction of DNA damage via ATM/γ-H2AX; and 4) decrease in DNA methytransferase (DNMT) and global methylation. RNA interference study shows a predominant role of DNMT1 in MM cell survival versus DNMT3a or DNMT3b. Deubiquitylating enzyme USP7 stimulates DNMT1 activity; and conversely, USP7-siRNA reduced DNMT1 activity and decreased MM cell viability. RRx-001 plus USP7 inhibitor P5091 triggered synergistic anti-MM activity. MM xenograft studies show that RRx-001 is well tolerated, inhibits tumor growth, and enhances survival. Combining RRx-001 with pomalidomide, bortezomib or SAHA induces synergistic anti-MM activity. Our results provide the rationale for translation of RRx-001, either alone or in combination, to clinical evaluation in MM.