Chapter 5 │ Page 178 suggests a chemoprotective mechanism mediated by heterologous Cx43-GJs in advanced cancer stages, and inhibition of this interaction has therapeutic potential. In addition to the role of GJs to improve chemotherapy, Vance and Wiley suggested that ionizing radiation destroys not only targeted cells but also cells that have not been directly irradiated (the bystander e ect) [125], and this e ect is partially regulated by GJs [42], prompting GJIC as an appealing therapeutic target in combinatorial strategies with radiotherapy [126-128]. Zhang et al. found that iodideinduced upregulation of Cx43 protein expression and Cx43-GJ activity in genetically-modified non-small cell lung cancer cells significantly increased the bystander tumoricidal e ects generated by ionizing radiation, thereby enhancing tumor cell killing both in vitro and in vivo [43]. Furthermore, the authors suggested that iodide could also modulate a cascade of molecular pathways including RONS signaling through Cx43-GJs, to further sensitize non-small cell lung cancer cells to ionizing radiation and chemotherapies like paclitaxel [43]. In concordance, experimental evidence suggested that GJs enhance the intercellular propagation of "death signals", thereby expanding therapeutical cytotoxicity (Figure 1a) [126-128]. Krutovskikh et al. observed that GJs propagate and increase cell death in rat bladder carcinoma cells, a cellular model that is predisposed to spontaneous apoptosis upon achieving confluency, by spreading cell-killing signals initially generated by a single apoptotic cell into healthy (non-apoptotic) surrounding cells [40]. In depth studies with a neuropeptide (oleamide) that selectively restricted GJs permeability to Ca2+ ions showed that the cell death spreading was not prevented upon administration while Lucifer yellow dye transfer was blocked, suggesting that Ca2+ ions were the most probable cell-killing signals spread through GJs [40]. In summary, therapies that modulate Cxs and GJs could be a promising anti-cancer strategy, especially in combination with other conventional treatments such as chemotherapy and radiotherapy. However, further delineation of the conditions in
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