Abstract C213: Eribulin, vincristine, ixabepilone, and paclitaxel inhibit neuronal cell function by varied mechanisms and to varying degrees.

Chemotherapy-induced peripheral neuropathy (CIPN) is a common adverse effect of cancer treatment with microtubule-targeting drugs (MTDs). It is often dose limiting and negatively affects quality of life. To understand the mechanisms of CIPN, we examined the effects of four MTDs, eribulin, vincristine, ixabepilone, and paclitaxel, on cell death and neurite extension in vitro using an immortalized rat sensory neuronal cell line (50B11) and the drug effects on microtubule-based axonal transport in isolated squid axoplasm. Although paclitaxel and ixabepilone have similar microtubule-based mechanisms of action and induce similar levels of CIPN clinically, using an ATP-based cell death assay we found that paclitaxel was significantly more toxic to 50B11 neuronal cells in vitro than ixabepilone. Paclitaxel killed cells at concentrations 35 times lower than ixabepilone (IC509s, 0.2 nM and 7 nM, respectively). Vincristine also had high levels of cell killing (IC50, 0.4 nM). Eribulin induced neuronal 50B11 cell killing (IC50, 0.8 nM), but less than vincristine or paclitaxel. All four drugs caused retraction of 50B11 cell neurites in vitro, with the order of potency being vincristine>eribulin>ixabepilone>paclitaxel. Paclitaxel and ixabepilone, which stabilize microtubules rather than depolymerizing them at high concentrations, required approximately 10-fold higher concentrations for neurite retraction than eribulin. The effects of the four drugs on axonal transport were analyzed in isolated, extruded cytoplasmic membrane-free squid axoplasm at concentrations similar to those observed intracellularly. Ixabepilone and vincristine significantly reduced both anterograde and retrograde axonal transport at a low concentration (1 μM), but eribulin and paclitaxel did not. Eribulin and paclitaxel required a higher concentration to inhibit transport (10 μM), and reduced only anterograde transport, while leaving retrograde transport unaffected. Our results to date indicate that the mechanisms responsible for inhibition of neuronal function by the four MTDs vary substantially. In summary, vincristine and eribulin affected in vitro neuronal cell function by multiple mechanisms, inducing neurite retraction and cell death, with vincristine having a stronger effect than eribulin. Vincristine inhibited axonal transport significantly more strongly than eribulin, which had very little effect on transport. Paclitaxel potently killed neuronal cells, but had very little effect on axonal transport. In contrast, ixabepilone strongly inhibited axonal transport but had only a weak neuronal cell killing effect. These results are based solely on in vitro research and clinical trials have not been performed to support these findings. Testing other aspects of induction of peripheral neuropathy is in progress. Supported by a grant from Eisai Inc. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr C213.