Chapter 5 │ Page 183 enhance intracellular RONS, increasing membrane permeability and eventually apoptotic cell death. Intracellular protein kinases can also a ect the connexon opening probability [149,150], so small molecules that can trigger the activation of intracellular protein kinases could also indirectly modulate connexon activity. Hence, a potential approach in cancer therapy would be to enhance the connexon open state to improve oxidative stress-mediated cell death, though more studies focusing on the biophysical properties of potential connexon activators are necessary to improve their selectivity, solubility, permeability, and pharmacodynamics. An open state of connexons can also contribute to the release of RONS and/or the activation of other signaling pathways which have a protective mechanism against cell death [33,151,152]. For example, H2O2-induced oxidative stress opened Cx43 proteins-composed connexons in lens epithelial cells, mediating the exchange of oxidants and antioxidants in these cells undergoing oxidative stress [33]. These transporting activities facilitated a reduction of intracellular RONS accumulation and maintained the intracellular glutathione level, protecting lens against oxidative stress to prevent cataract formation during aging [33]. One therapeutic strategy to avoid this protective mechanism in cancer cells could be to design inhibitors that block connexons from opening during RONS-mediated oxidative stress, to increase intracellular accumulation of RONS (Figure 5.3). In this way, monoclonal antibodies to the EL-2 loop of Cx43 proteins (173-208 amino acid residues) were developed, and they were demonstrated to block connexons from opening in glioma cells [153]. Moreover, these antibodies inhibited GJs formation, indicating that they react with target connexon solely [153]. Furthermore, it was shown that glioma cells presenting Cx43 proteins were more resistant to H2O2-induced oxidative stress, due to inhibition of caspase-3 activation; Cx43 proteins interacted with the upstream apoptosis signal-regulating kinase 1, known to mediate H2O2-induced apoptosis, providing a possible mechanism for the anti-apoptotic e ect [151]. Interestingly,
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