Neurotoxicity of the antineoplastic drugs: "Doxorubicin" as an example

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.