Blockade of the forward Na+/Ca2+ exchanger suppresses the growth of glioblastoma cells through Ca2+-mediated cell death
Blockade of the forward Na+/Ca2+ exchanger suppresses the growth of glioblastoma cells through Ca2+-mediated cell death
复制标题
阻断前向 Na /Ca2 交换器可通过 Ca2 介导的细胞死亡抑制胶质母细胞瘤细胞的生长
DOI：
10.1111/bph.14692
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发表时间：
2019-08-01
影响因子：
7.3
通讯作者：
Song, Mingke
中科院分区：
文献类型：
--
作者：
Hu, Hui-Jie;Wang, Shan-Shan;Song, Mingke
背景与目的Na+/Ca 2+交换器（NCX）以正向或反向方式参与维持细胞内Ca 2+（[Ca 2 +]（i））稳态，对细胞命运起决定作用。以前，已经开发了许多靶向反向或正向NCX的阻滞剂，并在缺血性组织损伤中进行了研究，但几乎没有在胶质母细胞瘤中进行抗肿瘤治疗。我们评估了NCX阻断剂对胶质母细胞瘤生长的影响以及NCX是否可以成为治疗靶点。实验方法采用膜片钳技术、钙离子成像技术、流式细胞术和Western blot技术研究特异性和非特异性NCX阻断剂对体外培养的胶质母细胞瘤细胞的作用。体内生物发光成像用于测量对移植的胶质母细胞瘤的影响。用SEA 0400、SN-6和YM-244769选择性阻断反向NCX不影响肿瘤细胞活力。用苄普地尔、CB-DMB或KB-R7943阻断正向NCX升高[Ca 2 +]（i）并杀死胶质母细胞瘤细胞。苄普地尔和CB-DMB引起钙依赖性细胞周期阻滞和凋亡，这都被钙螯合剂BAPTA-AM减弱。苄普地尔全身给药抑制脑移植胶质母细胞瘤的生长。苄普地尔似乎对人星形胶质细胞没有细胞毒性作用，星形胶质细胞比胶质母细胞瘤细胞具有更高的NCX功能表达。结论NCX低表达使胶质母细胞瘤细胞对[Ca 2 +]（i）的紊乱敏感。旨在阻断前向NCX的干预措施可能会导致Ca 2+介导的胶质母细胞瘤损伤，因此具有治疗潜力。苄普地尔可能是开发新的抗肿瘤药物的先导化合物。
Background and Purpose The Na+/Ca2+ exchanger (NCX) working in either forward or reverse mode participates in maintaining intracellular Ca2+ ([Ca2+](i)) homeostasis, which is essential for determining cell fate. Previously, numerous blockers targeting reverse or forward NCX have been developed and studied in ischaemic tissue injury but barely examined in glioblastoma for the purpose of anti-tumour therapy. We assessed the effect of NCX blockers on glioblastoma growth and whether NCX can become a therapeutic target. Experimental Approach Patch-clamp recording, Ca2+ imaging, flow cytometry, and Western blot were used to study the effects of specific and non-specific NCX blockers on cultured glioblastoma cells. In vivo bioluminescent imaging was used to measure effects on grafted glioblastoma. Key Results Selectively blocking the reverse NCX with SEA0400, SN-6, and YM-244769 did not affect tumour cell viability. Blocking the forward NCX with bepridil, CB-DMB, or KB-R7943 elevated [Ca2+](i) and killed glioblastoma cells. Bepridil and CB-DMB caused Ca2+-dependent cell cycle arrest together with apoptosis, which were all attenuated by a Ca2+ chelator BAPTA-AM. Systemic administration of bepridil inhibited growth of brain-grafted glioblastoma. Bepridil did not appear to have a cytotoxic effect on human astrocytes, which have higher functional expression of NCX than glioblastoma cells. Conclusions and Implications Low expression of the NCX makes glioblastoma cells sensitive to disturbance of [Ca2+](i). Interventions designed to block the forward NCX can cause Ca2+-mediated injury to glioblastoma thus having therapeutic potential. Bepridil could be a lead compound for developing new anti-tumour drugs.