Chong-Zhi Wang1,2, Chunping Wan3,4, Yun Luo4, Chun-Feng Zhang5, Qi-Hui Zhang6, Lina Chen7, Zhi Liu4, Daniel H Wang4, Mallory Lager4, Cang-Hai Li8, Ting-Liang Jiang8, Lifei Hou9, Chun-Su Yuan4,10. 1. Central Laboratory, The No. 1 Affiliated Hospital of Yunnan University of Traditional Chinese Medicine, Kunming, 650021, China. czwang@dacc.uchicago.edu. 2. Tang Center for Herbal Medicine Research, and Department of Anesthesia and Critical Care, University of Chicago, 5841 South Maryland Avenue, MC 4028, Chicago, IL, 60637, USA. czwang@dacc.uchicago.edu. 3. Central Laboratory, The No. 1 Affiliated Hospital of Yunnan University of Traditional Chinese Medicine, Kunming, 650021, China. 4. Tang Center for Herbal Medicine Research, and Department of Anesthesia and Critical Care, University of Chicago, 5841 South Maryland Avenue, MC 4028, Chicago, IL, 60637, USA. 5. School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, 210009, Jiangsu, China. 6. School of Chemistry and Chemical Engineering, Chongqing University, Chongqing, 400044, China. 7. School of Pharmacy, Nanjing Medical University, Nanjing, 211166, Jiangsu, China. 8. Tang Center for Traditional Chinese Medicine Research, Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, 100700, China. 9. Program in Cellular and Molecular Medicine, Boston Children's Hospital and Department of Pediatrics, Harvard Medical School, Boston, MA, 02115, USA. 10. Committee on Clinical Pharmacology and Pharmacogenomics, University of Chicago, Chicago, IL, 60637, USA.
Abstract
BACKGROUND: Artemisinin (ART) is an anti-malaria natural compound with a moderate anticancer action. As a metabolite of ART, dihydroartemisinin (DHA) may have stronger anti-colorectal cancer (CRC) bioactivities. However, the effects of DHA and ART on CRC chemoprevention, including adaptive immune regulation, have not been systematically evaluated and compared. METHODS: Coupled with a newly-established HPLC analytical method, enteric microbiome biotransformation was conducted to identify if the DHA is a gut microbial metabolite of ART. The anti-CRC potential of these compounds was compared using two different human CRC cell lines for cell cycle arrest, apoptotic induction, and anti-inflammation activities. Naive CD4+ T cells were also obtained for testing the compounds on the differentiation of Treg, Th1 and Th17. RESULTS: Using compound extraction and analytical methods, we observed for the first time that ART completely converted into its metabolites by gut microbiome within 24 h, but no DHA was detected. Although ART did not obviously influence cancer cell growth in the concentration tested, DHA very significantly inhibited the cancer cell growth at relatively low concentrations. DHA included G2/M cell cycle arrest via upregulation of cyclin A and apoptosis. Both ART and DHA downregulated the pro-inflammatory cytokine expression. The DHA significantly promoted Treg cell proliferation, while both ART and DHA inhibited Th1 and Th17 cell differentiation. CONCLUSIONS: As a metabolite of ART, DHA possessed stronger anti-CRC activities. The DHA significantly inhibited cell growth via cell cycle arrest, apoptosis induction and anti-inflammation actions. The adaptive immune regulation is a related mechanism of actions for the observed effects.
BACKGROUND: Artemisinin (ART) is an anti-malaria natural compound with a moderate anticancer action. As a metabolite of ART, dihydroartemisinin (DHA) may have stronger anti-colorectal cancer (CRC) bioactivities. However, the effects of DHA and ART on CRC chemoprevention, including adaptive immune regulation, have not been systematically evaluated and compared. METHODS: Coupled with a newly-established HPLC analytical method, enteric microbiome biotransformation was conducted to identify if the DHA is a gut microbial metabolite of ART. The anti-CRC potential of these compounds was compared using two different human CRC cell lines for cell cycle arrest, apoptotic induction, and anti-inflammation activities. Naive CD4+ T cells were also obtained for testing the compounds on the differentiation of Treg, Th1 and Th17. RESULTS: Using compound extraction and analytical methods, we observed for the first time that ART completely converted into its metabolites by gut microbiome within 24 h, but no DHA was detected. Although ART did not obviously influence cancer cell growth in the concentration tested, DHA very significantly inhibited the cancer cell growth at relatively low concentrations. DHA included G2/M cell cycle arrest via upregulation of cyclin A and apoptosis. Both ART and DHA downregulated the pro-inflammatory cytokine expression. The DHA significantly promoted Treg cell proliferation, while both ART and DHA inhibited Th1 and Th17 cell differentiation. CONCLUSIONS: As a metabolite of ART, DHA possessed stronger anti-CRC activities. The DHA significantly inhibited cell growth via cell cycle arrest, apoptosis induction and anti-inflammation actions. The adaptive immune regulation is a related mechanism of actions for the observed effects.