Neurotoxic Mechanisms of the Chemotherapeutic Paclitaxel

Chemotherapy-induced peripheral neuropathy (CIPN) is a common dose-limiting side effect of multiple chemotherapeutic agents for which there are currently no prevention strategies. The widely used chemotherapeutic paclitaxel causes CIPN, which involves degeneration of sensory axons in the skin and loss of sensation and ongoing pain in the hands and feet. Paclitaxel is known to bind and stabilize microtubules, but the cellular mechanisms that underlie paclitaxel’s neurotoxic effects are not well understood. To advance the understanding of molecular mechanisms of paclitaxel neurotoxicity, I used a culture system of clinically relevant adult mammalian sensory neurons to interrogate hypotheses for putative neurotoxic mechanisms. Paclitaxel exposure in cultured sensory neurons caused arrest of axon growth and formation of retraction bulb-like swellings at axonal endings, and I took this in vitro phenotype to be a likely correlate of the degeneration that occurs in vivo. As the first step in defining a mechanistic pathway starting with paclitaxel exposure and ending with degeneration of axons, I asked whether paclitaxel’s neurotoxic effects were due to its microtubule stabilizing activity or to an off-target effect. By correlating the toxicity and microtubule stabilizing activity of structurally different microtubule stabilizing compounds, I find that microtubule hyperstabilization is the likely primary cause of paclitaxel neurotoxicity. I went on to investigate the causative role of potential downstream effects of microtubule stabilization in paclitaxel neurotoxicity, and my results challenge hypotheses that had been put forth in the literature. I find that changes in tubulin posttranslational modifications, although present after paclitaxel exposure, are not causal for paclitaxel-induced neurotoxic effects in culture, and changes in axonal transport are also unlikely to play an early causative role in the degeneration. By selectively treating different parts of the axon with paclitaxel, I find that the distal axon is primarily vulnerable to paclitaxel, indicating that paclitaxel acts directly on the distal axon to induce degenerative effects. Overall, my findings point to local effects of microtubule hyperstabilization on the cellular function of the distal axon as an early mediator of paclitaxel neurotoxicity. These studies further our understanding of the mechanisms responsible for paclitaxel’s toxic effects on neurons, and thus contribute to the knowledge required in the effort to develop strategies for CIPN prevention.Medical Science