Dihydroartemisinin inhibits melanoma by regulating CTL/Treg anti-tumor immunity and STAT3-mediated apoptosis via IL-10 dependent manner

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-g + 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 + Tcells were normalized by DHA treatment. DHA diminished expression of IL-10 and IL-6, and increased the expression of IFN-g 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.

Characterization of a Tumor-Microenvironment-Relevant Gene Set Based on Tumor Severity in Colon Cancer and Evaluation of Its Potential for Dihydroartemisinin Targeting

“…The data presented above, in addition to many studies in the literature, indicate that DHA is involved in regulating the TME of cancer [ 16 , 26 ]. However, there is no publicly available information about the role of DHA in the TME of COAD.…”

“…Previous studies showed that DHA could inhibit COAD cell viability through regulating cell proliferation and apoptosis [15,42]. e data presented above, in addition to many studies in the literature, indicate that DHA is involved in regulating the TME of cancer [16,26]. However, there is no publicly available information about the role of DHA in the TME of COAD.…”

“…DHA has potential antitumor therapeutic effects across human cancers through inhibition of cancer cell proliferation, migration, and invasion capabilities. DHA was proposed to regulate the TME in head and neck cancer, breast cancer, and melanoma [ 16 , 25 , 26 ]. However, the effect of DHA in the TME of COAD has not been previously described.…”

Dihydroartemisinin inhibits activation of the AIM2 inflammasome pathway and NF-κB/HIF-1α/VEGF pathway by inducing autophagy in A431 human cutaneous squamous cell carcinoma cells

“…In recent years, the anticancer effects of DHA have also been confirmed in a variety of tumor models. With regard to skin cancer, the inhibitory effects of DHA on the growth of cSCC and melanoma cells have been preliminarily confirmed [22][23][24]. Its anticancer mechanisms have been shown to be diverse, including the promotion of apoptosis, activation of endoplasmic reticulum stress, acceleration of Fe 2+ -induced oxidative damage, and promotion of autophagy in cancer cells [21,35,36].…”

“…Dihydroartemisinin (DHA) is a derivative of artemisinin and has been widely used as an antimalarial drug [18]. Meanwhile, it has also been reported to exert therapeutic effects against cancers [19][20][21][22][23][24]. DHA promotes cell apoptosis and inhibits cell proliferation by inducing autophagy in various carcinoma cells, including cervical carcinoma, cholangiocarcinoma, and hepatocellular carcinoma [19][20][21].…”