Introduction: Gap junction protein Connexin 43 (Cx43) appears to confer resistance of glioblastomas to Temozolamide (TMZ)- particularly in tumors that recur after initially responding to therapy. We sought to study whether inhibition of Cx43 would restore glioblastoma cell sensitivity to TMZ. We tested this using a selective CX43 semi-channel inhibitor peptide known as alpha CT1

Methods: Fresh glioblastoma specimens were obtained from a series of patients undergoing surgery at our institution. TMZ resistant Glioblastoma cell lines were cultured as were derivative stem cells (GSCs), and were studied with respect to prominence of CX43. Mice were inoculated with GSCs. Cell viability in culture and in inoculated mice was then evaluated after exposure to TMZ and alphaCT1 vs TMZ or alphaCT1 alone.

Results: Both in culture and in inoculated mice glioblastoma cell and derivative stem cell growth was substantially blocked by the combination of TMZ and alphaCT1 but not by TMZ or alphaCT1 alone.

Conclusions: CX43 is thought to confer resistance of glioblastoma cells and their stem cell lines to Temozolomide. In this study we were able to show increased tumor cell sensitivity to Temozolomide by blocking CX43 with the peptide alphaCT1. This selective CX43 hemi-channel inhibitor may prove to be an effective adjunct to TMZ in the treatment of glioblastoma. This may be particularly true for recurrent glioblastoma.

Patient Care: potential contribution to glioblastoma therapy

Learning Objectives: to search for novel new treatments of glioblastoma to see if inhibition of CX43 would confer greater sensitivity to glioblastoma cells and their stem cell lines

References: Gielen, P. R., Aftab, Q., Ma, N., Chen, V. C., Hong, X., Lozinsky, S., Naus, C. C., and Sin, W. C. (2013) Connexin43 confers Temozolomide resistance in human glioma cells by modulating the mitochondrial apoptosis pathway. Neuropharmacology 75, 539-548