Eicosapentaenoic acids enhance chemosensitivity through connexin 43 upregulation in murine melanoma models

Abstract

Chemotherapy is now in common use for the treatment of tumors; however, with tumor growth retardation comes the severe side effects that occur after a chemotherapy cycle. Eicosapentaenoic acids (EPA) used in combination with chemotherapy has an additive effects and provides a rationale for using EPA in tandem with chemotherapy. To improve the efficacy and safety of this combination therapy, a further understanding that EPA modulates with the tumor microenvironment is necessary. Connexin 43 (Cx43) is involved in enhancing chemosensitivity that was suppressed in a tumor microenvironment. We aim to investigate the role of EPA in chemosensitivity in murine melanoma by inducing Cx43 expression. The dose-dependent upregulation of Cx43 expression and gap junction intercellular communication were observed in B16F10 cells after EPA treatment. Furthermore, EPA significantly increased the expression levels of mitogen-activated protein kinases (MAPK) signaling pathways. The EPA-induced Cx43 expression was reduced after MAPK inhibitors. Knockdown Cx43 in B16F10 cells reduced the therapeutic effects of combination therapy (EPA plus 5-Fluorouracil). Our results demonstrate that the treatment of EPA is a tumor induced Cx43 gap junction communication and enhances the combination of EPA and chemotherapeutic effects.

The extracts of Astragalus membranaceus enhance chemosensitivity and reduce tumor indoleamine 2, 3-dioxygenase expression

“…Tumors can utilize multiple strategies to evade the immune response, requiring an appropriate method that involves a combination of targets to improve therapeutic outcomes. We explored the potential to enhance the tumor therapeutic response through Cx43 and IDO pathway inhibition in different tumor types including melanoma and lung cancer 25, 26. Recently, we also observed that PG2 could inhibit the expression of programmed cell death protein 1 ligand 1 (PD-L1) in tumor cells (unpublished data).…”

Connexins in melanoma: Potential role of Cx46 in its aggressiveness

“…The combination of resveratrol with cisplatin causes a potentiated apoptotic effect in vitro, and reduced tumor cell growth to a higher extent than cisplatin therapy alone in vivo (Cheng et al, 2015). Similar results were obtained using regular 5-FU anticancer therapy in combination with eicosapentaenoic acids (EPA) that upregulate Cx43, enhancing the drug cytotoxicity through the activation of mitogen-activated protein kinase (MAPK) signaling pathways (Yang et al, 2019). In addition, the bystander effect is the basis of gene suicide therapy success, where dying cells share toxic substrates via GJCs to neighbor cells, promoting massive cell death (Nardin et al, 2019).…”

The Influences of Omega-3 Polyunsaturated Fatty Acids on the Development of Skin Cancers

“…It is suppressed in the tumor microenvironment. EPA improves chemosensitivity in murine melanoma by inducing connexin 43 expression, which is regulated by MAPK pathways [47]. In addition, DHA enhances the sensitivity of various tumor cells to ROS-inducing anti-cancer agents [48].…”

“…In addition, omega-3 PUFAs suppress tumor growth in melanoma [32,37,41,42,44,45] and squamous cell carcinoma [77], inhibiting migration and invasion in melanoma [33,34,37] and squamous cell carcinoma [81]. Omega-3 PUFAs also enhance the sensitivity to chemotherapy in melanoma [28][29][30][31][46][47][48] and radiosensitivity in squamous cell carcinoma [78]. Omega-3 PUFAs metabolites RvD1, RvD2, and RvE1 suppress debris-stimulated cancer progression in melanoma [50], and RvD2 reduces tumor size and cancer-derived cytokines/chemokines [76].…”