Ezzo Maya, Etienne-Manneville Sandrine
Cell Polarity, Migration and Cancer Unit, Institut Pasteur, UMR3691 CNRS, Université de Paris, Equipe Labellisée Ligue Contre le Cancer 2023, F-75015 Paris, France.
Int J Mol Sci. 2025 Aug 7;26(15):7652. doi: 10.3390/ijms26157652.
Microtubules play a key role in cell division and cell migration. Thus, microtubule-targeting agents (MTAs) are pivotal in cancer therapy due to their ability to disrupt cell division microtubule dynamics. Traditionally divided into stabilizers and destabilizers, MTAs are increasingly being repurposed for central nervous system (CNS) applications, including brain malignancies such as gliomas and neurodegenerative diseases like Alzheimer's and Parkinson's. Microtubule-stabilizing agents, such as taxanes and epothilones, promote microtubule assembly and have shown efficacy in both tumour suppression and neuronal repair, though their CNS use is hindered by blood-brain barrier (BBB) permeability and neurotoxicity. Destabilizing agents, including colchicine-site and vinca domain binders, offer potent anticancer effects but pose greater risks for neuronal toxicity. This review highlights the mapping of nine distinct tubulin binding pockets-including classical (taxane, vinca, colchicine) and emerging (tumabulin, pironetin) sites-that offer new pharmacological entry points. We summarize the recent advances in structural biology and drug design, enabling MTAs to move beyond anti-mitotic roles, unlocking applications in both cancer and neurodegeneration for next-generation MTAs with enhanced specificity and BBB penetration. We further discuss the therapeutic potential of combination strategies, including MTAs with radiation, histone deacetylase (HDAC) inhibitors, or antibody-drug conjugates, that show synergistic effects in glioblastoma models. Furthermore, innovative delivery systems like nanoparticles and liposomes are enhancing CNS drug delivery. Overall, MTAs continue to evolve as multifunctional tools with expanding applications across oncology and neurology, with future therapies focusing on optimizing efficacy, reducing toxicity, and overcoming therapeutic resistance in brain-related diseases.
微管在细胞分裂和细胞迁移中起着关键作用。因此，微管靶向剂（MTAs）在癌症治疗中至关重要，因为它们能够破坏细胞分裂微管动力学。MTAs传统上分为稳定剂和去稳定剂，越来越多地被重新用于中枢神经系统（CNS）应用，包括脑恶性肿瘤如神经胶质瘤以及神经退行性疾病如阿尔茨海默病和帕金森病。微管稳定剂，如紫杉烷类和埃坡霉素，促进微管组装，在肿瘤抑制和神经元修复方面均显示出疗效，但其在中枢神经系统的应用受到血脑屏障（BBB）通透性和神经毒性的阻碍。去稳定剂，包括秋水仙碱位点和长春花结构域结合剂，具有强大的抗癌作用，但对神经元毒性的风险更大。本综述重点介绍了九个不同的微管蛋白结合口袋的图谱，包括经典（紫杉烷、长春花、秋水仙碱）和新兴（图巴替尼、吡咯替尼）位点，这些位点提供了新的药理学切入点。我们总结了结构生物学和药物设计方面的最新进展，使MTAs能够超越抗有丝分裂作用，为具有更高特异性和血脑屏障穿透性的下一代MTAs在癌症和神经退行性疾病中解锁应用。我们进一步讨论了联合策略的治疗潜力，包括MTAs与放疗、组蛋白脱乙酰酶（HDAC）抑制剂或抗体药物偶联物的联合，这些联合在胶质母细胞瘤模型中显示出协同效应。此外，纳米颗粒和脂质体等创新递送系统正在增强中枢神经系统药物递送。总体而言，MTAs作为多功能工具不断发展，在肿瘤学和神经病学中的应用不断扩大，未来的治疗将专注于优化疗效、降低毒性以及克服脑部相关疾病的治疗耐药性。
