Background: The treatment landscape for multiple myeloma (MM) has significantly evolved in recent decades with novel therapies like proteasome inhibitors, immunomodulatory drugs and monoclonal antibodies. However, MM remains incurable, necessitating new pharmacological strategies. Mitotic kinases, such as Aurora proteins, have emerged as potential targets. Selective inhibitors of Aurora A and B,- alisertib (MLN8237) and barasertib (AZD1152), respectively, have shown anti-myeloma activity in preclinical studies, with alisertib demonstrating modest efficacy in early clinical trials. Methods and Results: This study investigated the mechanisms of action of alisertib and barasertib and their combination with antitumor agents in a panel of five MM cells lines. Both drugs induced cell cycle arrest phase and abnormal nuclear morphologies. Alisertib caused prolonged mitotic arrest, whereas barasertib induced transient arrest, both resulting in the activation of mitotic catastrophe. These findings revealed three potential outcomes: cell death, senescence, or polyploidy. High mitochondrial reactive oxygen species (mROS) were identified as possible drivers of cell death. Caspase inhibition reduced caspase-3 activation but did not prevent cell death. Interestingly, alisertib at low doses remained toxic to Bax/BakDKOcells, although mitochondrial potential disruption and cytochrome c release were observed. Sequential combinations of high-dose Aurora kinase inhibitors with BH3-mimetics, and in specific cases with panobinostat, showed a synergistic effect. Conversely, the simultaneous combination of alisertib and barasertib showed mostly antagonistic effects. Conclusions: Alisertib and barasertib emerge as potential in vitro candidates against MM, although further studies are needed to validate their efficacy and to find the best combinations with other molecules.
背景：近几十年来，多发性骨髓瘤（MM）的治疗格局因蛋白酶体抑制剂、免疫调节药物和单克隆抗体等新型疗法而显著演变。然而，MM目前仍无法治愈，需要新的药物策略。有丝分裂激酶，如Aurora蛋白，已成为潜在的治疗靶点。Aurora A和B的选择性抑制剂——分别为阿利塞替（MLN8237）和巴拉塞替（AZD1152）——在临床前研究中显示出抗骨髓瘤活性，其中阿利塞替在早期临床试验中表现出一定的疗效。 方法与结果：本研究在五种MM细胞系中探讨了阿利塞替和巴拉塞替的作用机制及其与抗肿瘤药物的联合应用。两种药物均诱导细胞周期阻滞和异常核形态。阿利塞替导致有丝分裂长期阻滞，而巴拉塞替则诱导短暂阻滞，两者均激活了有丝分裂灾难。这些发现揭示了三种潜在结果：细胞死亡、衰老或多倍体。高线粒体活性氧（mROS）被确定为细胞死亡的可能驱动因素。Caspase抑制减少了caspase-3的激活，但未能阻止细胞死亡。有趣的是，低剂量的阿利塞替对Bax/Bak双敲除细胞仍具有毒性，尽管观察到线粒体电位破坏和细胞色素c释放。高剂量Aurora激酶抑制剂与BH3模拟物序贯联合，以及在特定情况下与帕比司他联合，显示出协同效应。相反，阿利塞替和巴拉塞替同时联合则主要表现出拮抗作用。 结论：阿利塞替和巴拉塞替在体外显示出作为抗MM候选药物的潜力，但仍需进一步研究以验证其疗效并寻找与其他分子的最佳联合方案。
肿瘤(癌症)患者之家