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Lin, J.H., Weigel, H., Cotrina, M.L., Liu, S., Bueno, E., Hansen, A.J., Hansen, T.W., Goldman, S. and Nedergaard, M. (1998) Gap-Junction-Mediated Propagation and Amplification of Cell Injury. Nature Neuroscience, 1, 494-500. http://dx.doi.org/10.1038/2210

has been cited by the following article:

• TITLE: Gap Junctional Intercellular Communication Increases Cytotoxicity and Reduces Resistance to Hydroxyurea

  AUTHORS: Randall J. Ruch, Paul D. Boucher, Brian G. Gentry, Donna S. Shewach

  KEYWORDS: Bystander Effect, Drug Resistance, Gap Junctions, Hydroxyurea, Ribonucleotide Reductase

  JOURNAL NAME: Journal of Cancer Therapy, Vol.5 No.13, November 7, 2014

  ABSTRACT: Background: Gap junctions enable small molecules to diffuse between adjacent cells and have been associated with greater cytotoxicity of radiation and anti-cancer drugs. We investigatedwhether this gap junctional intercellular communication (GJIC) affected the cytotoxicity of the classicribonucleotide reductase (RR) inhibitor and anti-cancer agent, hydroxyurea (HU). Materials and Methods: We used GJIC-proficient and deficient, connexin 43-expressing WB rat liver epithelial cell lines. We compared HU toxicity by crystal violet assay, effects of the drug on deoxynucleotide pools by HPLC, and ability of GJIC to increase toxicity of HU-resistant cells through a bystander effect in co-culture experiments. Results: GJIC-proficient cells were three- to five-fold more sensitive (IC500.1 mM) to HU than GJIC-deficient derivatives (IC500.3 - 0.5 mM). This sensitivity depended upon GJIC because treatment of GJIC-proficient cells with the GJIC blocker oleamide decreased HU toxicity by approximately 60% - 80% and restoration of GJIC in GJIC-deficient cells by stable transduction of connexin 32-encodingGjb1increased HU toxicity (IC500.1 mM). The effects were not due to connexin expressionper seor its localization since all cell lines expressed comparable quantities of connexin 43 that was localized to the plasma membrane. Also HU sensitivity was not related to differential effects on nucleotide metabolism in the cells. Thymidine triphosphate levels increased and deoxyadenosine triphosphate levels decreased similarly (15% - 20%) in GJIC-proficient and deficient cells over 24 h of HU treatment. More importantly, when HU-resistant cells were co-cultured with sensitive cells, the resistant cells were killed only when GJICwas present. Conclusion: The data suggest that GJIC enhances cytotoxicity and decreases resistanceto HU. These results may be important clinically if GJIC can be enhanced in drug-resistant cells.