Artesunate exerts an anti‐immunosuppressive effect on cervical cancer by inhibiting PGE₂ production and Foxp3 expression

Abstract

Artesunate (ART), derived from a common traditional Chinese medicine, has beeen used an antimalarial for several years. In this study, the effect and mechanism of ART on anti-human cervical cancer cells was examined. The level of prostaglandin E2 (PGE2 ) and the population of CD4+CD25+Foxp3 regulatory T cells (Treg) in peripheral blood were detected by flow cytometry. In vivo antitumor activity was investigated in mice with cervical cancer by the subcutaneous injection of various concentrations of ART. The concentrations of PGE2 in the supernatants of CaSki cells were measured using an ELISA kit. Cyclooxygenase-2 (COX-2) and Foxp3 expression were determined using quantitative polymerase chain reaction (qPCR) and western blot analysis. The effect of ART on the viability of CaSki and Hela cells was evaluated with a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. It was identified that the level of PGE2 and the population of CD4+CD25+Foxp3 Treg cells in the peripheral blood were significantly higher in cervical cancer patients and mice with cervical cancer. ART was capable of inhibiting orthotopic tumor growth, which correlated with a decrease in the level of PGE2 and the percentage of Treg cells in mice with cervical cancer. Furthermore, ART decreased COX-2 expression and the production of PGE2 in CaSki and Hela cells. Notably, the supernatants of CaSki cells treated with ART lowered the expression of Foxp3 in Jurkat T cells, which was capable of being reversed by exogenous PGE2 . Our data revealed that ART may elicit an anti-tumor effect against cervical cancer by inhibition of PGE2 production in CaSki and Hela cells, which resulted in the decrease of Foxp3 expression in T cells. Therefore, ART may be an effective drug for immunotherapy of cervical cancer.

Artemisinin as an anticancer drug: Recent advances in target profiling and mechanisms of action

“…The general pattern of Treg depletion following artemisinin exposure was supported by Zhang et al. in their 2014 study that reported a similar depletion of CD4 + CD25 + FOXP3 + Treg in mouse cervical cancer models, with a corresponding inhibition of PGE 2 (prostaglandin E2) production and FOXP3 downregulation . This reduction in PGE 2 corroborates with a subsequent study in smooth muscle cells .…”

Naturally occurring anti-cancer compounds: shining from Chinese herbal medicine

“…As an analog of ART, artesunate exerts better water solubility and higher oral bioavailability, due to its special structure with an additional hemisuccinate group that makes it a better candidate for cancer treatment [668]. The anti-cancer effects of artesunate have been demonstrated in bladder, breast, cervical, colorectal, esophageal, gastric, ovarian and prostate cancer, renal carcinoma, leukemia, melanoma and multiple myeloma [179,[669][670][671][672][673][674][675][676][677][678][679]. Its anti-cancer effects include induction of cell cycle arrest and apoptosis, inhibition of cell proliferation and growth, metastasis and angiogenesis [670,678,680].…”

Artesunate Induces Apoptosis of Bladder Cancer Cells by miR-16 Regulation of COX-2 Expression

“…However, in the present study, we used 20, 100, and 200 mg/kg of ART to treat rats with bladder cancer. Moreover, Zhang et al reported that ART at the dose of 50 and 100 mg/kg could inhibit the growth of cervical cancer, which resulted from inhibiting activity of regulatory T cells through PGE2 [25]. We speculate that the difference in the concentrations levels of ART necessary for malaria treatment compared to the treatment of tumors is due to ART not being attracted specifically to tumor sites.…”