Chapter 5 │ Page 186 acids present in connexons and a ect the function of GJs? One method to investigate these questions is through the use of computational simulations. Xu et al. demonstrated the possible interaction of HO● and HO2 ● with the NT domain of a Cx26 proteins-composed connexon via reactive MD simulations. They found that these radicals chemically react with the amino acids within the NT domain of Cx26 proteins, and can structurally damage them [162]. Considering the negative e ects of Cxs and/or GJs upregulation in later cancer stages, structural damage induced by RONS can influence the e ectiveness of GJs-mediated tumoricidal activities. In addition, Xu et al. also supported the hypothesis that NTP-generated RONS trigger the bystander e ect based on GJs, highlighting again the potential role of GJs to propagate oxidative stress-mediated cell death [162]. However, additional studies will be necessary to elucidate the e ects of connexon oxidation on GJs properties, as well as the mechanism of RONS transportation through GJs. Bagati et al., reported additive-to-synergistic e ects of a NTP combination therapy with the DNA-damaging agent tirapazamine in in vitro and in vivo metastatic melanoma cells, which underline the potential of NTP to improve cancer therapy via GJ modulation [163]. The authors observed that when high Cx26-GJs expression was induced in these cells, the combinatorial e ects of NTP + tirapazamine therapy was augmented, spreading cell death. The presence of Cx26-GJs facilitated RONS cell penetration and signaling, while increased Cx26 protein expression and amplified tumoricidal activity [163]. Furthermore, they also observed an immune response through di erential regulation of cytokines and chemokines, suggesting potential for this therapy to induce a cytotoxic immune response [163]. Using a modified non-thermal helium plasma torch, the same research group showed that Cx43-GJs also contributes to NTP-induced cell death in melanoma cells [164]. They observed a higher sensitivity of these cells to RONS and a 6-fold increase in cell death by apoptosis compared with human keratinocytes [164]. Moreover, they
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