Chapter 5 │ Page 177 The use of Cxs-targeting antibodies has been another strategy to inhibit pathological GJ function and improve cancer therapies. Monoclonal antibodies to the EL-2 loop of Cx43 proteins (MAbE2Cx43) are intensively studied for human glioblastoma. Using a human glioblastoma rat model, MAbE2Cx43 monotherapy led to significant tumor reduction and prolonged animal survival, presumably via inhibition of specific functions of Cx43 proteins in the peritumoral zone [24]. Treatment with MAbE2Cx43 in combination with radiotherapy further inhibited tumor development and prolonged the median survival, likely due to the increase in blood-brain barrier permeability for antibodies after irradiation of the brain and inhibition of migration and/or signaling pathways [18]. Interestingly, MAbE2Cx43temozolomide combination therapy attenuated the tumor-suppressive activity of both monotherapies. Since a portion of the cytotoxic drugs penetrate into the cell through connexon gating, MAbE2Cx43 binding and blocking of Cx43-GJ formation could a ect the permeation of drugs like temozolomide into the cells [18]. These results highlight that combinatorial strategies using antibodies can be used to improve standard-of-care therapies like chemotherapy and radiation, however competitive inhibition of binding sites by MAbE2Cx43 needs to be circumvented to overcome antagonistic treatment e ects. Heterologous GJs established between cancer cells and healthy cell populations are reported to promote tumor spreading and treatment resistance, making them interesting targets for therapeutic intervention (Figure 1c, see figure caption for more details) [26,124]. Chen et al. demonstrated that breast and lung cancer cells were able to establish Cx43-GJs with astrocytes, promoting brain metastasis. Once the heterologous GJs were formed, cancer cells transferred the secondary messenger cGAMP to the healthy brain cells, thereby triggering paracrine signaling to promote tumor growth and chemoresistance [26]. Two modulators of GJs (i.e. meclofenamate and tonabersat) broke this paracrine loop, shown by inhibiting dye transfer from astrocytes to cancer cells and brain metastases [26]. This result
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