Reed Cinthia N, Garrison Kaylee B, Thammathong Joshua, Cinatl Jindrich, Michaelis Martin, Banerjee Souvik, Weissmiller April M
Department of Biology, Middle Tennessee State University, Murfreesboro, TN 37132, USA.
Department of Chemistry, Middle Tennessee State University, Murfreesboro, TN 37132, USA.
Molecules. 2025 May 16;30(10):2186. doi: 10.3390/molecules30102186.
High-risk neuroblastoma remains a clinically challenging pediatric cancer, with an approximate five-year survival rate of ~60%. Frontline therapy for this group of patients includes surgery and intensive chemotherapy that involves combinations of the tubulin inhibitor vincristine with several other chemotherapeutics. Unfortunately, unresponsiveness to therapy and relapse are common, with tumors often displaying resistance to vincristine. Recently, we characterized a novel set of tubulin inhibitors that are distinct from vincristine and bind within the colchicine binding site present on tubulin monomers. Colchicine binding site inhibitors (CBSIs) have gained traction as improved chemotherapeutics due to their potential to overcome tubulin inhibitor-induced resistance. In this study, we investigate the functional impact of CBSI treatment on multiple neuroblastoma cell lines, including those that are vincristine-resistant. We demonstrate that our newly developed compounds are effective at disrupting cell division in non-resistant and resistant cells and have cellular activity against vincristine-resistant cell lines. Interestingly, we find that vincristine-resistant cell lines differ in their ability to undergo apoptotic cell death in response to CBSI treatment. Taken together, these findings provide a solid foundation to further investigate the utility of CBSIs for neuroblastoma treatment, while highlighting the distinct resistance mechanisms that can emerge in these childhood cancers.
高危神经母细胞瘤仍然是一种临床上具有挑战性的儿科癌症，其五年生存率约为60%。这类患者的一线治疗包括手术和强化化疗，其中涉及微管蛋白抑制剂长春新碱与其他几种化疗药物的联合使用。不幸的是，对治疗无反应和复发很常见，肿瘤往往对长春新碱表现出耐药性。最近，我们鉴定了一组新型的微管蛋白抑制剂，它们与长春新碱不同，且结合在微管蛋白单体上存在的秋水仙碱结合位点内。秋水仙碱结合位点抑制剂（CBSIs）由于具有克服微管蛋白抑制剂诱导的耐药性的潜力，作为改良的化疗药物受到了关注。在这项研究中，我们研究了CBSI治疗对多种神经母细胞瘤细胞系的功能影响，包括那些对长春新碱耐药的细胞系。我们证明，我们新开发的化合物能够有效地破坏非耐药和耐药细胞中的细胞分裂，并对长春新碱耐药细胞系具有细胞活性。有趣的是，我们发现长春新碱耐药细胞系对CBSI治疗的凋亡细胞死亡反应能力有所不同。综上所述，这些发现为进一步研究CBSIs在神经母细胞瘤治疗中的效用提供了坚实的基础，同时突出了这些儿童癌症中可能出现的不同耐药机制。
