Chapter 5 │ Page 175 5. THERAPEUTIC STRATEGIES APPLIED TO Cxs AND GJs Novel combination strategies to restore GJs and Cx properties as tumorsuppressors in early cancer stages, or inhibit these structures in advanced stages when they display a tumor-supportive role have been studied to improve standardof-care treatments such as chemotherapy and radiotherapy. While chemotherapy is limited by drug toxicity and development of therapy resistance [118], novel multi-modal approaches to improve treatment response and tolerance are under investigation. Herein, stimulation of Cxs and GJs expression, via gene therapy, has been explored to potentialize anti-cancer drug activity in cancer cells. For instance, Cx43 gene therapy, in which the Cx43 gene is transfected into target cells to promote expression, has been demonstrated to increase cell sensitivity to several chemotherapeutics agents, in di erent cancer types [16,119,120]. In prostate cancer, the combination of Cx43-expressing plasmid DNA and the chemotherapeutic agent docetaxel had significantly stronger anticancer e ects compared to docetaxel alone, both in vitro and in vivo [16]. Notably, transfection of Cx43 proteins into the cells without docetaxel neither inhibited tumor growth nor increased GJs. However, combination therapy of Cx43 protein upregulation and docetaxel significantly inhibited cell growth and induced apoptotic cell death by downregulation of Bcl-2 expression, a protein that regulates cell apoptosis; and upregulation of caspase-3 activity, a protein which induces apoptosis, compared to docetaxel alone [16]. Later, gene therapy in colorectal cancer showed that Cx43 protein upregulation improves sensitivity for the chemotherapeutic drug paclitaxel. Transfection of Cx43 into the cells increased GJ function and subsequently the mitotic arrest, tubulin polymerization, and apoptotic e ects of paclitaxel, compared to cells treated with paclitaxel or Cx43 proteins alone [119]. Cell death was induced by activation of the caspase-3 apoptotic pathway [119]. More recently, similar results were found in breast cancer, in which
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