Oxidative stress and cancer pain1

Breast cancers are the most common source of metastases to bone, of which cancer-induced bone pain is a frequent pathological feature. Cancer-induced bone pain is a unique pain state with multiple determinants that remains to be well understood and managed. Current standard treatments are limited by dose-dependent side effects that can reduce the quality of life of patients. Glutamate is a neurotransmitter and bone cell-signalling molecule that is released via the system x(c)(-) cystine/glutamate antiporter from cancer cell types that frequently metastasize to bone, including breast cancers. In cancer cells, glutamate release is understood to be a side effect of the cellular response to oxidative stress that upregulates the expression and activity of system x(c)(-) to promote the increased import of cystine. Attenuation of glutamate release from cancer cells has been demonstrated to result in reductions in associated cancer-induced bone pain in animal models. This review examines the clinical implications of attenuating cystine uptake and glutamate release in the treatment of cancer-induced bone pain.