Blockade of the forward Na+/Ca2+ exchanger suppresses the growth of glioblastoma cells through Ca2+‐mediated cell death

Article date: August 2019

By: Hui‐Jie Hu, Shan‐Shan Wang, Yan‐Xia Wang, Yan Liu, Xue‐Mei Feng, Ying Shen, Liang Zhu, Hong‐Zhuan Chen, Mingke Song in Volume 176, Issue 15, pages 2691-2707

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.

DOI: 10.1111/bph.14692

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