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Int J Med Sci. 2019 May 7;16(5):636-643. doi: 10.7150/ijms.30889. eCollection 2019.

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

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Department of Internal Medicine, Kaohsiung Municipal Ta-Tung Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan.
Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan.
Faculty of Medicine, Department of Respiratory Therapy, College of Medicine, Kaohsiung Medical University, Taiwan.
Department of Microbiology and Immunology, National Cheng Kung University Medical College, Tainan, Taiwan.
Department of Biological Sciences, National Sun Yat-sen University, Kaohsiung, Taiwan.
Faculty of Pharmacy, Mahidol University, Bangkok, Thailand.
Department of Biotechnology, Kaohsiung Medical University, Kaohsiung, Taiwan.
Graduate Institute of Biomedical Sciences, College of Medicine, China Medical University, Taichung, Taiwan.
Center for Molecular Medicine, China Medical University Hospital, Taichung, Taiwan.
Department of Medical Research, China Medical University Hospital, China Medical University, Taichung, Taiwan.


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.


5-Fluorouracil; Connexin 43; Eicosapentaenoic acids; combination therapy

Conflict of interest statement

Competing Interests: The authors have declared that no competing interest exists.

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