Abstract：
Despite significant improvement in the prognosis of multiple myeloma (MM), the disease remains incurable; thus, more effective therapies are required. Ribonucleoside-diphosphate reductase subunit M2 (RRM2) is significantly associated with drug resistance, rapid relapse, and poor prognosis. Previously, we found that 4-hydroxysalicylanilide (osalmid), a specific inhibitor of RRM2, exhibits anti-MM activity in vitro, in vivo, and in human patients; however, the mechanism remains unclear. Osalmid inhibits the translocation of RRM2 to the nucleus and stimulates autophagosome synthesis but inhibits subsequent autophagosome-lysosome fusion. We confirm that RRM2 binds to receptor-interacting protein kinase 3 (RIPK3) and reduces RIPK3, inhibiting autophagosome-lysosome fusion. Interestingly, the combination of osalmid and bafilomycin A1 (an autophagy inhibitor) depletes RIPK3 and aggravates p62 and autophagosome accumulation, leading to autophagic cell death. Combination therapy demonstrates synergistic cytotoxicity both in vitro and in vivo. Therefore, we propose that combining osalmid and bafilomycin A1(BafA1) may have clinical benefits against MM.
摘要：
尽管多发性骨髓瘤（MM）的预后显着改善，这种疾病仍然无法治愈；因此，需要更有效的治疗方法。核糖核苷-二磷酸还原酶亚基M2（RRM2）的表达与耐药性显着相关，快速复发，预后不良。以前,我们发现4-羟基水杨酰苯胺（osalmid），RRM2的特异性抑制剂，在体外表现出抗MM活性，在体内，在人类患者中；然而，机制尚不清楚。Osalmid抑制RRM2向细胞核的易位并刺激自噬体合成,但抑制随后的自噬体-溶酶体融合。我们证实RRM2与受体相互作用蛋白激酶3（RIPK3）结合并减少RIPK3，抑制自噬体-溶酶体融合。有趣的是,osalmid和bafilomycinA1（一种自噬抑制剂）的联合使用会消耗RIPK3并加剧p62和自噬体的积累，导致细胞自噬性死亡.联合治疗在体外和体内都显示出协同的细胞毒性。因此,我们建议，将osalmid和bafilomycinA1（BafA1）联合使用可能对MM具有临床益处。
