Peripheral neuropathy induced by paclitaxel: in vitro study

Paclitaxel induced peripheral neuropathy (PIPN) is a severe adverse effect observed in most cancer patients receiving paclitaxel for the treatment of breast, ovarian or lung cancer (1). In cancer cells, paclitaxel induces cell death via microtubule stabilization interrupting cell mitosis. Although highly effective in blocking tumor progression, a major dose-limiting side effect of paclitaxel can persist for up to two years after completing treatment, greatly affecting both the course of chemotherapy and patients' quality of life. The main symptoms of PIPN are numbness, paresthesia and burning pain in a glove-and-stocking distribution. Recent studies have aimed at defining the underlying mechanisms of PIPN. In vitro models using dorsal root ganglion (DRG) neurons have revealed a number of molecular pathways affected by paclitaxel within axons of sensory neurons, such as altered calcium signaling, neuropeptide and growth factor release, mitochondrial damage, reactive oxygen species formation, activated ion channels that mediate responses to extracellular cues and role for the matrix-metalloproteinase 13 in mediating neuropathy (2, 3). In this study, DRG derived sensory neuron culture system obtained from adult rats as a useful in vitro model, has been used to recapitulate the pathophysiological features of peripheral neuropathy and axonal degeneration. One of the most notable effects of paclitaxel neurotoxicity in DRG in vitro models is the reduction of neurite length. DRG dissociated primary cultures have been used as a neurotoxicity-screening model to evaluate the effect of paclitaxel on the neurite elongation.  The neurotoxic effect of this drug was analyzed by measuring the neurite length of post-mitotic, non-dividing cells, such as neurons. Paclitaxel-induced tubulin polymerization in these cells is thought to interfere with axonal transport, causing peripheral neuropathy. The neurotoxic effect of paclitaxel is dose and time dependent. Moreover, in DRG dissociated post-mitotic neurons, the morphological features of paclitaxel-induced cellular death were studied and the DRG neurons were observed to die by necrosis. DRG derived sensory neurons, as well as DRG explants are a good, simple and well-accepted model for studying peripheral neuropathy induced by various antineoplastic agents. Drug neurotoxicity assessment in vitro is based on the ability of post-mitotic cells to outgrow and prolong neurites when exposed to toxic substances. Currently, there are no therapeutic options available for the prevention or successful therapy of PIPN and only few drugs are recommended for the treatment of existing neuropathies because the mechanisms of PIPN remain unclear. Our findings demonstrate a previously known neurotoxic effect of paclitaxel in DRG derived sensory neuron culture system and suggest advantages of this in vitro model, as high efficiency and reproducibility of cell culture studies in the field of toxic neuropathy induced by paclitaxel.