Lange Ingo, Espinoza-Fuenzalida Italo, Ali Mourad Wagdy, Serrano Laura Espana, Koomoa Dana-Lynn T
University of Hawaii at Hilo, The Daniel K. Inouye College of Pharmacy, Hilo, HI 96720, USA.
Oncotarget. 2017 Nov 6;8(66):109985-109999. doi: 10.18632/oncotarget.22452. eCollection 2017 Dec 15.
Neuroblastoma (NB) is the most common extra-cranial pediatric solid tumor. High-risk NB is difficult to treat due to the lack of response to current therapies and aggressive disease progression. Despite novel drugs, alternative treatments and multi-modal treatments, finding an effective treatment strategy for these patients continues to be a major challenge. The current study focuses on examining the effects of FTY-720 or fingolimod, a drug that is FDA-approved for refractory multiple sclerosis, in NB. The results showed that FTY-720 regulates multiple pathways that result in various effects on calcium signaling, ion channel activation and cell survival/death pathways. FTY-720 rapidly inhibits TRPM7 channel activity, and inhibited TRPM7 kinase activity, modulates calcium signaling, induces a loss of mitochondrial membrane potential and opening of the mitochondrial permeability transition pore, and ultimately leads to cell death. Interestingly, the data also showed that low concentrations of FTY-720 sensitized drug-resistant NB cells to antineoplastic drugs. These results suggest that FTY-720 may be an attractive alternative for the treatment of NB.
神经母细胞瘤（NB）是最常见的儿童颅外实体瘤。高危NB由于对当前治疗缺乏反应以及疾病进展迅速而难以治疗。尽管有新型药物、替代治疗和多模式治疗，但为这些患者找到有效的治疗策略仍然是一项重大挑战。当前的研究聚焦于研究FTY-720（一种已获美国食品药品监督管理局批准用于治疗难治性多发性硬化症的药物）对NB的影响。结果表明，FTY-720调节多种信号通路，这些通路对钙信号、离子通道激活以及细胞存活/死亡通路产生各种影响。FTY-720迅速抑制瞬时受体电位阳离子通道亚家族M成员7（TRPM7）通道活性，抑制TRPM7激酶活性，调节钙信号，诱导线粒体膜电位丧失以及线粒体通透性转换孔开放，并最终导致细胞死亡。有趣的是，数据还显示低浓度的FTY-720使耐药NB细胞对抗肿瘤药物敏感。这些结果表明，FTY-720可能是治疗NB的一种有吸引力的替代方案。
