Ran Yu1, Linbo Jin1, Fangfang Li1, Manabu Fujimoto2, Qiang Wei1, Zhenhua Lin3, Xiangshan Ren3, Quanxin Jin1, Honghua Li1, Fanping Meng1, Guihua Jin4. 1. Department of Immunology and Pathogenic Biology, Yanbian University Medical College, Yanji, China. 2. Department of Dermatology, Graduate School of Medicine, Osaka University, Laboratory of Cutaneous Immunology, Osaka UniversityImmunology Frontier Research Center, Osaka, Japan. 3. Department of Pathology, Yanbian University Medical College, Yanji, China. 4. Department of Immunology and Pathogenic Biology, Yanbian University Medical College, Yanji, China. Electronic address: ghjin@ybu.edu.cn.
Abstract
BACKGROUND: It has been shown that dihydroartemisinin (DHA) is effective in the treatment of malaria. Recently studies have demonstrated that DHA also regulates tumor cell growth, angiogenesis, T cell differentiation and generation. However, how DHA affects melanoma development remains poorly defined. OBJECTIVES: To investigate the effects of DHA on the proliferation and migration of melanoma in vivo and in vitro, and to explore its possible mechanism. METHODS: B16F10 cells and melanoma-bearing BALB/c mice were used to investigate the effects of DHA on melanoma. RESULTS: DHA had inhibitory effect on melanoma proliferation in a time-and dose-dependent manner. Treatment of DHA attenuated melanoma severity and histopathological changes in BALB/c mice. DHA also inhibited melanoma invasion, migration, and community formation in a dose-dependent manner. Flow cytometry revealed a significant increase in IFN-γ+CD8+ T cells in the DHA groups. In tumor microenvironment and spleen, DHA induced expansion of CD8+CTL, while, CD4+CD25+Foxp3+ regulatory T (Treg) cells and IL-10+CD4+CD25+ T cells were normalized by DHA treatment. DHA diminished expression of IL-10 and IL-6, and increased the expression of IFN-γ in the tumor and spleen. Moreover, DHA administration significantly promoted the mitochondrial apoptosis of melanoma by regulating the STAT3 pathway. CONCLUSION: DHA induces mitochondrial apoptosis and alters cytokines expression by inhibiting the phosphorylation of STAT3. DHA improves anti-tumor immunity in mice through controlling CD8+CTL function by counteracting IL-10-dependent Treg cells suppression, which promises to be an alternative drug for melanoma.
BACKGROUND: It has been shown that dihydroartemisinin (DHA) is effective in the treatment of malaria. Recently studies have demonstrated that DHA also regulates tumor cell growth, angiogenesis, T cell differentiation and generation. However, how DHA affects melanoma development remains poorly defined. OBJECTIVES: To investigate the effects of DHA on the proliferation and migration of melanoma in vivo and in vitro, and to explore its possible mechanism. METHODS:B16F10 cells and melanoma-bearing BALB/c mice were used to investigate the effects of DHA on melanoma. RESULTS:DHA had inhibitory effect on melanoma proliferation in a time-and dose-dependent manner. Treatment of DHA attenuated melanoma severity and histopathological changes in BALB/c mice. DHA also inhibited melanoma invasion, migration, and community formation in a dose-dependent manner. Flow cytometry revealed a significant increase in IFN-γ+CD8+ T cells in the DHA groups. In tumor microenvironment and spleen, DHA induced expansion of CD8+CTL, while, CD4+CD25+Foxp3+ regulatory T (Treg) cells and IL-10+CD4+CD25+ T cells were normalized by DHA treatment. DHA diminished expression of IL-10 and IL-6, and increased the expression of IFN-γ in the tumor and spleen. Moreover, DHA administration significantly promoted the mitochondrial apoptosis of melanoma by regulating the STAT3 pathway. CONCLUSION:DHA induces mitochondrial apoptosis and alters cytokines expression by inhibiting the phosphorylation of STAT3. DHA improves anti-tumor immunity in mice through controlling CD8+CTL function by counteracting IL-10-dependent Treg cells suppression, which promises to be an alternative drug for melanoma.