State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Hai he Laboratory of Cell Ecosystem, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, PR China.
Tianjin Key Laboratory of Molecular Design and Drug Discovery, Tianjin Institute of Pharmaceutical Research, Tianjin 300301, PR China; State Key Laboratory of Drug Delivery Technology and Pharmacokinetics, Tianjin Institute of Pharmaceutical Research, Tianjin 300301, PR China.
EBioMedicine. 2022 Apr;78:103950. doi: 10.1016/j.ebiom.2022.103950. Epub 2022 Mar 26.
Multiple myeloma (MM) is still an incurable malignancy of plasma cells. Proteasome inhibitors (PIs) work as the backbone agent and have greatly improved the outcome in majority of newly diagnosed patients with myeloma. However, drug resistance remains the major obstacle causing treatment failure in clinical practice. Here, we investigated the effects of Indirubin-3'-monoxime (I3MO), one of the derivatives of Indirubin, in the treatment of MM.
MM patient primary samples and human cell lines were examined. I3MO effects on myeloma treatment and the underling molecular mechanisms were investigated via in vivo and in vitro study.
Our results demonstrated the anti-MM activity of I3MO in both drug- sensitive and -resistance MM cells. I3MO sensitizes MM cells to bortezomib-induced apoptosis. Mechanistically, I3MO acts as a multifaceted regulator of cell death, which induced DNA damage, cell cycle arrest, and abrogates NF-κB activation. I3MO efficiently down-regulated USP7 expression, promoted NEK2 degradation, and suppressed NF-κB signaling in MM. Our study reported that I3MO directly bound with and caused the down-regulation of PA28γ (PSME3), and PA200 (PSME4), the proteasome activators. Knockdown of PSME3 or PSME4 caused the inhibition of proteasome capacity and the overload of paraprotein, which sensitizes MM cells to bortezomib-mediated growth arrest. Clinical data demonstrated that PSME3 and PSME4 are over-expressed in relapsed/refractory MM (RRMM) and associated with inferior outcome.
Altogether, our study indicates that I3MO is agent triggering proteasome inhibition and represents a promising therapeutic strategy to improve patient outcome in MM.
A full list of funding can be found in the acknowledgements.
多发性骨髓瘤（MM）仍然是一种不可治愈的浆细胞恶性肿瘤。蛋白酶体抑制剂（PIs）作为骨干药物，极大地改善了大多数新诊断骨髓瘤患者的预后。然而，耐药性仍然是导致临床治疗失败的主要障碍。在这里，我们研究了靛玉红-3'-单肟（I3MO）作为靛玉红衍生物之一在治疗 MM 中的作用。
检查 MM 患者原代样本和人细胞系。通过体内和体外研究，研究 I3MO 对骨髓瘤治疗的影响及其潜在的分子机制。
我们的结果表明，I3MO 对耐药和敏感的 MM 细胞均具有抗 MM 活性。I3MO 可使 MM 细胞对硼替佐米诱导的凋亡敏感。在机制上，I3MO 作为细胞死亡的多方面调节剂，可诱导 DNA 损伤、细胞周期停滞，并抑制 NF-κB 激活。I3MO 可有效下调 USP7 表达，促进 NEK2 降解，并抑制 MM 中的 NF-κB 信号。我们的研究报告称，I3MO 可直接与并导致 PA28γ（PSME3）和 PA200（PSME4）下调，PA28γ（PSME3）和 PA200（PSME4）是蛋白酶体的激活剂。PSME3 或 PSME4 的敲低导致蛋白酶体能力抑制和副蛋白过载，从而使 MM 细胞对硼替佐米介导的生长停滞敏感。临床数据表明，PSME3 和 PSME4 在复发性/难治性 MM（RRMM）中过度表达，并与预后不良相关。
总之，我们的研究表明，I3MO 是一种触发蛋白酶体抑制的药物，代表了改善 MM 患者预后的一种很有前途的治疗策略。
完整的资助清单可以在致谢中找到。
