Inhibition of System Xc⁻ Reduces Cancer-Induced Bone Pain

Abstract

The most common cancer types have a high likelihood of metastasizing to the bone and can cause cancer-induced bone pain (CIBP). Current therapeutic options do not offer proper management and thus CIBP can severely affect a patient's quality of life. Dysregulation of the excitatory neurotransmitter, glutamate, may be involved in the complex and multifaceted mechanisms of CIBP. Because glutamatergic signaling promotes pain, a local rise in glutamate in the bone-tumor microenvironment may contribute to CIBP. Glutamate levels are regulated in part by the cystine/glutamate antiporter, system xc⁻. System xc⁻ is known to be expressed by many different cancer cell types. It functions by transporting cystine into cells and in return releasing glutamate into the extracellular space. Elevated glutamate levels driven by the upregulated expression of this antiporter may contribute to CIBP. Here we demonstrate that system xc⁻ is expressed on a spontaneously occurring murine mammary tumor cell line (66.1) and that treatment of these cells with the established inhibitor and anti-inflammatory agent, sulfasalazine, decreases glutamate secretion in a time and dose-dependent manner. Furthermore, in a novel model of breast CIBP, systemic sulfasalazine treatment not only reduces glutamate levels within the femur, but also significantly attenuates CIBP behaviors. Studies utilized 66.1 cells implanted into the femur intramedullary space of immunocompetent mice. Measurements of spontaneous and evoked pain were made 7 and 10 days post cancer cell inoculation. Systemic administration of sulfasalazine for 4 days (on days 7-10) significantly reduced spontaneous pain-related behaviors and glutamate in femur extrudate as compared to vehicle treated controls. In summary, we demonstrate that pharmacological inhibition of the system xc⁻ transporter attenuates CIBP related behaviors in mice. These data support a role for system xc⁻ in CIBP and validate it as an analgesic target. Further research is warranted to evaluate the potential repurposing of sulfasalazine as an antinociceptive agent for patients with CIBP.