Inhibition of Gap Junctions Sensitizes Primary Glioblastoma Cells for Temozolomide

• Main Authors: Anna-Laura Potthoff, Dieter Henrik Heiland, Bernd O. Evert, Filipe Rodrigues Almeida, Simon P. Behringer, Andreas Dolf, Ági Güresir, Erdem Güresir, Kevin Joseph, Torsten Pietsch, Patrick Schuss, Ulrich Herrlinger, Mike-Andrew Westhoff, Hartmut Vatter, Andreas Waha, Matthias Schneider
• Format: Article
• Language: English
• Published: MDPI AG 2019-06-01
• Series: Cancers
• Subjects: glioblastoma; gap junctions; INI-0602; cell death; c-Jun
• Online Access: https://www.mdpi.com/2072-6694/11/6/858

Gap junctions have recently been shown to interconnect glioblastoma cells to a multicellular syncytial network, thereby allowing intercellular communication over long distances as well as enabling glioblastoma cells to form routes for brain microinvasion. Against this backdrop gap junction-targeted therapies might provide for an essential contribution to isolate cancer cells within the brain, thus increasing the tumor cells’ vulnerability to the standard chemotherapeutic agent temozolomide. By utilizing INI-0602—a novel gap junction inhibitor optimized for crossing the blood brain barrier—in an oncological setting, the present study was aimed at evaluating the potential of gap junction-targeted therapy on primary human glioblastoma cell populations. Pharmacological inhibition of gap junctions profoundly sensitized primary glioblastoma cells to temozolomide-mediated cell death. On the molecular level, gap junction inhibition was associated with elevated activity of the JNK signaling pathway. With the use of a novel gap junction inhibitor capable of crossing the blood−brain barrier—thus constituting an auspicious drug for clinical applicability—these results may constitute a promising new therapeutic strategy in the field of current translational glioblastoma research.