Fazzari Jennifer, Balenko Matthew D, Zacal Natalie, Singh Gurmit
Department of Pathology and Molecular Medicine, McMaster University, Hamilton, ON, Canada.
J Pain Res. 2017 Apr 18;10:915-925. doi: 10.2147/JPR.S125045. eCollection 2017.
The cystine/glutamate antiporter has been implicated in a variety of cancers as a major mediator of redox homeostasis. The excess glutamate secreted by this transporter in aggressive cancer cells has been associated with cancer-induced bone pain (CIBP) from distal breast cancer metastases. High-throughput screening of small molecule inhibitors of glutamate release from breast cancer cells identified several potential compounds. One such compound, capsazepine (CPZ), was confirmed to inhibit the functional unit of system x (xCT) through its ability to block uptake of its radiolabeled substrate, cystine. Blockade of this antiporter induced production of reactive oxygen species (ROS) within 4 hours and induced cell death within 48 hours at concentrations exceeding 25 μM. Furthermore, cell death and ROS production were significantly reduced by co-treatment with N-acetylcysteine, suggesting that CPZ toxicity is associated with ROS-induced cell death. These data suggest that CPZ can modulate system x activity in vitro and this translates into antinociception in an in vivo model of CIBP where systemic administration of CPZ successfully delayed the onset and reversed CIBP-induced nociceptive behaviors resulting from intrafemoral MDA-MB-231 tumors.
胱氨酸/谷氨酸逆向转运体作为氧化还原稳态的主要调节因子，已被证实与多种癌症相关。这种转运体在侵袭性癌细胞中分泌的过量谷氨酸，与远端乳腺癌转移引起的癌症诱导性骨痛（CIBP）有关。通过高通量筛选乳腺癌细胞中谷氨酸释放的小分子抑制剂，鉴定出了几种潜在化合物。其中一种化合物，辣椒素（CPZ），通过其阻断放射性标记底物胱氨酸摄取的能力，被证实可抑制系统x（xCT）功能单位。在浓度超过25μM时，该逆向转运体的阻断在4小时内诱导活性氧（ROS）生成，并在48小时内诱导细胞死亡。此外，通过与N-乙酰半胱氨酸共同处理，细胞死亡和ROS生成显著减少，表明CPZ毒性与ROS诱导的细胞死亡有关。这些数据表明，CPZ可在体外调节系统x活性，这在CIBP体内模型中转化为镇痛作用，即全身给予CPZ成功延迟了由股内MDA-MB-231肿瘤引起的CIBP发作并逆转了其伤害性反应行为。
