Cell metabolomics analyses revealed a role of altered fatty acid oxidation in neurotoxicity pattern difference between nab-paclitaxel and solvent-based paclitaxel

Abstract

Peripheral neuropathy (PN) is a dose-limiting, painful adverse reaction associated with the use of paclitaxel. This common side effect was often partially attributed to the solvent used for solubilization of the highly hydrophobic drug substance. Therefore, the development of alternative formulations thrived, which included that of Abraxane® containing nanoparticle albumin-bound paclitaxel (nab-paclitaxel). However, studies demonstrated inconsistent conclusions regarding the mitigation of PN in comparison with the traditional formulation. The mass spectrometry-based cell metabolomics approach was used in the present study to explore the potentially associated mechanisms. Although no significant difference in the effects on cell viability was observed, fold changes in carnitine, several acylcarnitines and long-chain fatty acid(s) were significantly different between treatment groups in differentiated and undifferentiated SH-SY5Y cells. The most prominent difference observed was the significant increase of octanoylcarnitine in cells treated with solvent-based paclitaxel, which was found to be associated with significant decrease of medium-chain acyl-CoA dehydrogenase (MCAD). The findings suggested the potential role of altered fatty acid oxidation in the different neurotoxicity patterns observed, which may be a possible target for therapeutic interventions worth further investigation.

Effect of age on metabolomic changes in a model of paclitaxel‐induced peripheral neurotoxicity

“…These findings point to the major involvement of lipid compounds in support of drug-stress, as a necessary source of energy, leading to a significant production of reactive oxygen species from the β-oxidation pathway eventually resulting in mitochondrial impairment, and excitotoxicity. [29][30][31] In support of mitochondrial dysfunction, we also observed decreased levels of acylcarnitines at the end of the follow-up period in young treated animals. Altered plasma levels of acylcarnitines can be found as a consequence of incompletely oxidized fatty acids due to an overload of beta oxidation ability and associated pathways, driving perturbations in mitochondrial fuel utilization, as well as a consequence of oxidative stress.…”

“…Specifically, multivariate analysis showed that both young and adult treated animals presented lower levels of triglycerides and diglycerides following paclitaxel administration compared to controls. These findings point to the major involvement of lipid compounds in support of drug‐stress, as a necessary source of energy, leading to a significant production of reactive oxygen species from the β‐oxidation pathway eventually resulting in mitochondrial impairment, and excitotoxicity 29–31 …”

Toxicometabolomics: Small Molecules to Answer Big Toxicological Questions

“…Studies on drug-induced neurotoxicity are still very limited, although in vitro/in vivo experiments have already demonstrated the benefits and utility of metabolomics to comprehensively detect and characterize neurotoxicity and discover new biomarkers [ 134 , 135 , 136 ]. For example, in a study conducted by van Vliet et al [ 134 ], rat primary reaggregating brain cell cultures were treated for 48 h with the neurotoxicant methyl mercury chloride (0.1–100 µM) or with the brain stimulant caffeine (1–100 µM), and subsequently, the cellular metabolic profiles were analyzed by LC-MS.…”

A Multimodal Approach to Discover Biomarkers for Taxane-Induced Peripheral Neuropathy (TIPN): A Study Protocol

“…There are few studies describing metabolic changes from taxanes and their role in the pathogenesis of neuropathic pain, and to our knowledge, only a single study specific to paclitaxel. 88 A cell-based metabolomics survey performed in neuroblastoma cells suggested a potential role of altered fatty acid oxidation in different neurotoxicity patterns observed such as neuropathic pain induced by paclitaxel treatment. 88 However, the role of metabolites deriving from other drugs, such as oxaliplatin, have been implicated to be involved in the etiology of CIPN.…”

“…88 A cell-based metabolomics survey performed in neuroblastoma cells suggested a potential role of altered fatty acid oxidation in different neurotoxicity patterns observed such as neuropathic pain induced by paclitaxel treatment. 88 However, the role of metabolites deriving from other drugs, such as oxaliplatin, have been implicated to be involved in the etiology of CIPN. For instance, oxalate (derived from oxaliplatin) alters calcium signaling leading to damage in intracellular structures in neuronal and glial cells.…”