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

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.