Silva João P N, Pinto Bárbara, Monteiro Luís, Silva Patrícia M A, Bousbaa Hassan
UNIPRO-Oral Pathology and Rehabilitation Research Unit, University Institute of Health Sciences (IUCS), Cooperativa de Ensino Superior Politécnico e Universitário (CESPU), Rua Central de Gandra, 1317, 4585-116 Gandra, Portugal.
Associate Laboratory i4HB, Institute for Health and Bioeconomy, University Institute of Health Sciences-CESPU, 4585-116 Gandra, Portugal.
Cancers (Basel). 2024 May 25;16(11):2014. doi: 10.3390/cancers16112014.
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.
许多调节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对有丝分裂期间纺锤体极的正确分离至关重要，而AurB在染色体分离和胞质分裂中发挥作用。靶向KSP和AurB的药物选择性地影响分裂细胞，并在体外显示出显著活性。然而，这些药物尽管已进入临床试验，但作为单一疗法往往产生不尽人意的结果，这可能是由于细胞周期蛋白B降解和凋亡信号积累网络导致的反应差异所致。积累的数据表明，与单一疗法相比，将新型抗有丝分裂药物与各种细胞周期抑制剂联合使用可增强肿瘤杀伤效果。在此，我们研究了用BH3模拟物Navitoclax抑制抗凋亡信号对用选择性KSP抑制剂Ispinesib或AurB抑制剂Barasertib处理的口腔癌细胞的影响，旨在增强细胞死亡。BH3模拟物与KSP和AurB抑制剂的联合使用协同诱导大量细胞死亡，主要通过凋亡实现。本文介绍了通过活细胞成像对这种协同活性进行的机制分析。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有效性的重要性。
