Ibrahim Fouad Ghadha, Rizk Maha Z
Department of Therapeutic Chemistry, Pharmaceutical and Drug Industries Research Institute, National Research Centre, 33 El-Bohouth St., Dokki, Cairo, 12622, Egypt.
J Mol Histol. 2024 Dec;55(6):1023-1050. doi: 10.1007/s10735-024-10247-9. Epub 2024 Oct 1.
There is an increased prevalence of cancer, and chemotherapy is widely and routinely utilized to manage the majority of cancers; however, administration of chemotherapeutic drugs has faced limitations concerning the "off-target" cytotoxicity. Chemobrain and impairment of neurocognitive functions have been observed in a significant fraction of cancer patients or survivors and reduce their life quality; this could be ascribed to the ability of chemotherapeutic drugs to alter the structure and function of the brain. Doxorubicin (DOX), an FDA-approved chemotherapeutic drug with therapeutic effectiveness, is commonly used to treat several carcinomas clinically. DOX-triggered neurotoxicity is the most serious adverse reaction after DOX-induced cardiotoxicity which greatly limits its clinical application. DOX-induced neurotoxicity is a net of multiple mechanisms that have been verified in pre-clinical and clinical studies, such as oxidative stress, neuroinflammation, mitochondrial disruption, apoptosis, autophagy, disruption of neurotransmitters, and impairment of neurogenesis. There is a massive need for developing novel therapeutics for both cancer and DOX-associated neurotoxicity; therefore investigating the implicated mechanisms of DOX-induced chemobrain will reveal multi-targets for novel curative strategies. Recently, various neuroprotective mechanisms were employed to mitigate DOX-mediated neurotoxicity. For this purpose, therapeutic interventions using pharmacological compounds were developed to protect healthy "off-target" tissues from DOX-induced toxicity. In addition, nanoplatforms were used to enable target delivery of DOX; to prevent its deposition in non-cancerous tissues. The aim of the current review is to provide some reference value for the future management of DOX-induced neurotoxicity and to summarize the underlying mechanisms of DOX-mediated neurotoxicity and the potential therapeutic interventions.
癌症的患病率呈上升趋势，化疗被广泛且常规地用于治疗大多数癌症；然而，化疗药物的给药在“脱靶”细胞毒性方面面临局限性。在相当一部分癌症患者或幸存者中观察到了化疗脑和神经认知功能受损的情况，这降低了他们的生活质量；这可能归因于化疗药物改变大脑结构和功能的能力。阿霉素（DOX）是一种经美国食品药品监督管理局（FDA）批准的具有治疗效果的化疗药物，临床上常用于治疗多种癌症。DOX引发的神经毒性是DOX诱导的心脏毒性之后最严重的不良反应，这极大地限制了其临床应用。DOX诱导的神经毒性是一个由多种机制构成的网络，这些机制已在临床前和临床研究中得到证实，如氧化应激、神经炎症、线粒体破坏、细胞凋亡、自噬、神经递质紊乱以及神经发生受损。迫切需要开发针对癌症和DOX相关神经毒性的新型疗法；因此，研究DOX诱导化疗脑的相关机制将揭示新型治疗策略的多个靶点。最近，人们采用了各种神经保护机制来减轻DOX介导的神经毒性。为此，开发了使用药理化合物的治疗干预措施，以保护健康的“脱靶”组织免受DOX诱导的毒性。此外，纳米平台被用于实现DOX的靶向递送；以防止其在非癌组织中沉积。本综述的目的是为未来DOX诱导神经毒性的管理提供一些参考价值，并总结DOX介导神经毒性的潜在机制和潜在的治疗干预措施。
