Sphingosine-1-phosphate signaling: A novel target for simultaneous adjuvant treatment of triple negative breast cancer and chemotherapy-induced neuropathic pain
Sphingosine-1-phosphate signaling: A novel target for simultaneous adjuvant treatment of triple negative breast cancer and chemotherapy-induced neuropathic pain
复制标题
DOI：
10.1016/j.jbior.2019.100670
复制
发表时间：
2020-01-01
影响因子：
--
通讯作者：
Spiegel, Sarah
中科院分区：
文献类型：
--
作者：
Singh, Sandeep K.;Spiegel, Sarah
三阴性乳腺癌(TNBC)侵袭性强，转移率和死亡率高，不幸的是，除化疗外，几乎没有治疗选择。神经鞘糖脂的生物活性代谢物-1-磷酸鞘氨醇(S1P)调节许多对癌症进展、转移和神经病理性疼痛至关重要的过程。用于治疗多发性硬化症的前体药物FTY720(Fingolimod，Gilenya)在体内被磷酸化成与S1PRs(S1PR2除外)结合的SIP模拟物，也是S1PR1的功能拮抗剂。这篇综述重点介绍了FTY720具有多种抗癌活性并同时防止S1P的形成和作用的最新研究结果。此外，在小鼠乳腺癌模型中，FTY720治疗减少了肿瘤的生长和转移，并提高了晚期荷尔蒙难治性乳腺癌和TNBC对传统疗法的敏感性。我们讨论了最近的研究表明，通过给予临床相关剂量的FTY720，很可能是通过靶向星形胶质细胞的S1PR1，化疗药物bortezomib引起的神经病理性疼痛也大大减少。FTY720在临床前研究中也显示出良好的抗癌潜力，并已获得FDA的批准，因此我们建议在这篇综述中需要进一步的研究，为快速批准FTY720/Fingolimod提高化疗有效性和减少痛苦的神经疾病铺平道路。
Triple-negative breast cancer (TNBC) is very aggressive with high metastatic and mortality rates and unfortunately, except for chemotherapy, there are few therapeutic options. The bioactive sphingolipid metabolite sphingosine-1-phosphate (S1P) regulates numerous processes important for cancer progression, metastasis, and neuropathic pain. The pro-drug FTY720 (fingolimod, Gilenya) used to treat multiple sclerosis is phosphorylated in the body to a SIP mimic that binds to S1PRs, except S1PR2, and also acts as a functional antagonist of S1PR1. This review highlights current findings showing that FTY720 has multiple anti-cancer activities and simultaneously prevents formation and actions of S1P. Moreover, in mouse breast cancer models, treatment with FTY720 reduces tumor growth, metastasis, and enhances sensitivity of advanced and hormonal refractory breast cancer and TNBC to conventional therapies. We discuss recent studies demonstrating that neuropathic pain induced by the chemotherapeutic bortezomib is also greatly reduced by administration of clinically relevant doses of FTY720, likely by targeting S1PR1 on astrocytes. FTY720 also shows promising anticancer potential in pre-clinical studies and is FDA approved, thus we suggest in this review that further studies are needed to pave the way for fast-tracking approval of FTY720/fingolimod for enhancing chemotherapy effectiveness and reduction of painful neuropathies.