Paclitaxel and vinorelbine, evoked the release of substance P from cultured rat dorsal root ganglion cells through different PKC isoform-sensitive ion channels

Abstract

Many patients suffer from serious adverse effects including respiratory distress and pulmonary edema during and after chemotherapy with paclitaxel or vinorelbine. These effects appear to be due to the activation of neurokinin-1 receptors. The present study investigated the influences of paclitaxel and vinorelbine on the substance P (sP) release from cultured dorsal root ganglion (DRG) cells using a radioimmunoassay. Both paclitaxel and vinorelbine evoked sP release in a dose- and time-dependent manner within 60 min at a concentration range of 0.1–10 μM. The sP release levels induced by the two drugs were attenuated by pretreatment with the protein kinase Cs (PKCs) inhibitors (bisindolylmaleimide I and Gö6976). Moreover, the paclitaxel- or vinorelbine-induced sP release was diminished in the absence of extracellular Ca 2+ or the presence of LaCl 3 (an extracellular Ca 2+ influx blocker). A Ca 2+ imaging assay further indicated that both paclitaxel and vinorelbine gradually increased the intracellular Ca 2+ concentration, and these increases lasted for at least 15 min and were suppressed by Gö6976. Paclitaxel caused the membrane translocation of only PKCβ within 10 min after stimulation, whereas vinorelbine induced the translocation of both PKCα and β. The paclitaxel- and vinorelbine-induced sP release levels were separately inhibited by ruthenium red (a transient receptor potential (TRP) channel blocker) and gabapentin (an inhibitor of voltage-gated Ca 2+ channels (VGCCs)). These findings suggest that paclitaxel and vinorelbine evoke the sP release from cultured DRG cells by the extracellular Ca 2+ influx through TRP channels activated by PKCβ and VGCCs activated by both PKCα and β, respectively.