Many proteins regulating mitosis have emerged as targets for cancer therapy, including the kinesin spindle protein (KSP) and Aurora kinase B (AurB). KSP is crucial for proper spindle pole separation during mitosis, while AurB plays roles in chromosome segregation and cytokinesis. Agents targeting KSP and AurB selectively affect dividing cells and have shown significant activity in vitro. However, these drugs, despite advancing to clinical trials, often yield unsatisfactory outcomes as monotherapy, likely due to variable responses driven by cyclin B degradation and apoptosis signal accumulation networks. Accumulated data suggest that combining emerging antimitotics with various cytostatic drugs can enhance tumor-killing effects compared to monotherapy. Here, we investigated the impact of inhibiting anti-apoptotic signals with the BH3-mimetic Navitoclax in oral cancer cells treated with the selective KSP inhibitor, Ispinesib, or AurB inhibitor, Barasertib, aiming to potentiate cell death. The combination of BH3-mimetics with both KSP and AurB inhibitors synergistically induced substantial cell death, primarily through apoptosis. A mechanistic analysis underlying this synergistic activity, undertaken by live-cell imaging, is presented. Our data underscore the importance of combining BH3-mimetics with antimitotics in clinical trials to maximize their effectiveness.
许多调控有丝分裂的蛋白质已成为癌症治疗的靶点，包括驱动蛋白纺锤体蛋白（KSP）和极光激酶B（AurB）。KSP在有丝分裂过程中对纺锤体极的正确分离至关重要，而AurB则在染色体分离和胞质分裂中发挥作用。靶向KSP和AurB的药物选择性影响分裂细胞，并在体外显示出显著活性。然而，尽管这些药物已进入临床试验阶段，但作为单一疗法往往效果不佳，这可能是由于细胞周期蛋白B降解和凋亡信号积累网络驱动的不同反应所致。积累的数据表明，与单一疗法相比，将新兴抗有丝分裂药物与各种细胞抑制药物联合使用可以增强肿瘤杀伤效果。本研究探讨了在经选择性KSP抑制剂Ispinesib或AurB抑制剂Barasertib处理的口腔癌细胞中，使用BH3模拟物Navitoclax抑制抗凋亡信号对增强细胞死亡的影响。BH3模拟物与KSP和AurB抑制剂的联合应用通过协同作用诱导了显著的细胞死亡，主要通过凋亡途径实现。通过活细胞成像技术，我们对这种协同作用的机制进行了分析。我们的数据强调了在临床试验中将BH3模拟物与抗有丝分裂药物联合使用以最大化其疗效的重要性。
肿瘤(癌症)患者之家