Targeting Ion Channels: Blockers Suppress Calcium Signals and Induce Cytotoxicity Across Medulloblastoma Cell Models.

in Bioengineering (Basel, Switzerland) by Darani Ashley Thammavongsa, Taylor N Jackvony, Markus J Bookland, Min D Tang-Schomer

TLDR

  • This study repurposed FDA-approved channel blockers and modulators to investigate their potential anti-tumor effects on medulloblastoma; it found that calcium signaling is critical for MB cell survival and that targeted inhibition of calcium pathways suppresses tumor cell growth.

Abstract

Medulloblastoma (MB) groups 3 and 4 lack targeted therapies despite their dismal prognoses. Ion channels and pumps have been implicated in promoting MB metastasis and growth; however, their roles remain poorly understood. In this study, we repurposed FDA-approved channel blockers and modulators to investigate their potential anti-tumor effects in MB cell lines (DAOY and D283) and primary cell cultures derived from a patient with MB. For the first time, we report spontaneous calcium signaling in MB cells. Spontaneous calcium signals were significantly reduced by mibefradil (calcium channel blocker), paxilline (calcium-activated potassium channel blocker), and thioridazine (potassium channel blocker). These drugs induced dose-dependent cytotoxicity in both the DAOY and D283 cell lines, as well as in primary cell cultures of a patient with group 3 or 4 MB. In contrast, digoxin and ouabain, inhibitors of the Na/K pump, reduced the calcium signaling by over 90% in DAOY cells and induced approximately 90% cell death in DAOY cells and 80% cell death in D283 cells. However, these effects were significantly diminished in the cells derived from a patient with MB, highlighting the variability in drug sensitivity among MB models. These findings demonstrate that calcium signaling is critical for MB cell survival and that the targeted inhibition of calcium pathways suppresses tumor cell growth across multiple MB models.

Overview

  • The study investigated the potential anti-tumor effects of FDA-approved channel blockers and modulators on medulloblastoma (MB) cell lines and primary cell cultures.
  • Spontaneous calcium signaling was reported in MB cells, which was significantly reduced by several drugs.
  • The study aimed to identify targeted therapies for MB groups 3 and 4, which lack effective treatments and have poor prognoses.

Comparative Analysis & Findings

  • The study found that calcium signaling is critical for MB cell survival and that targeted inhibition of calcium pathways suppresses tumor cell growth across multiple MB models.
  • Mibefradil, paxilline, and thioridazine significantly reduced spontaneous calcium signals and induced dose-dependent cytotoxicity in MB cell lines and primary cell cultures.
  • Digoxin and ouabain inhibited the Na/K pump, reducing calcium signaling by over 90% in some cell lines, but this effect was diminished in primary cell cultures derived from a patient with MB.

Implications and Future Directions

  • This study highlights the potential of repurposing FDA-approved channel blockers and modulators as targeted therapies for MB groups 3 and 4.
  • Further investigation is needed to understand the variability in drug sensitivity among MB models and to identify effective treatments for patients with poor prognoses.
  • The discovery of spontaneous calcium signaling in MB cells opens up new avenues for research into the molecular mechanisms of MB progression and development.
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