Huaier Extractum Promotes Dendritic Cells Maturation and Favors them to Induce Th1 Immune Response: One of the Mechanisms Underlying Its Anti-Tumor Activity.

Huaier, a sandy beige mushroom with anti-tumor effects, has been applied into Traditional Chinese Medicine for more than 1600 years. Previous studies showed that Huaier exerted its anti-tumor effects not only by direct action on tumor cells, but also indirectly by modulation of immune function. In the present study, we found that Huaier treatment significantly repressed tumor growth in mice with 4T1 breast cancer and resulted in significant accumulation of CD4+ T cells and mature dendritic cells (DCs) in the tumor microenvironment. In vitro experiments demonstrated that Huaier treatment promoted both DC2.4 and bone marrow derived DCs (BMDCs) to express costimulatory molecules, enhance production of IL-1ß and IL-12p70, while it inhibited their phagocytic activities, suggesting that Huaier treatment promotes maturation of DCs. Furthermore, we found Huaier-treated DCs profoundly stimulated proliferation of alloreactive CD4+ T cells and drove them to differentiate into Th1 subset. Expression of PI3K, Akt, p-Akt, JNK, and p-JNK was up-regulated, while p-p38 MAPK was down-regulated in Huaier-treated BMDCs, suggesting that Huaier promotes maturation of DCs with potent ability to activate Th1 immune response via modulation of MAPK and PI3K/Akt signaling pathways. Our findings provide further evidence for the mechanisms underlying the anti-tumor activity of Huaier.

Pharmacological inhibition of dihydroorotate dehydrogenase induces apoptosis and differentiation in acute myeloid leukemia cells.

Acute myeloid leukemia is a disorder characterized by abnormal differentiation of myeloid cells and a clonal proliferation derived from primitive hematopoietic stem cells. Interventions that overcome myeloid differentiation have been shown to be a promising therapeutic strategy for acute myeloid leukemia. In this study, we demonstrate that CRISPR/Cas9-mediated knockout of dihydroorotate dehydrogenase leads to apoptosis and normal differentiation of acute myeloid leukemia cells, indicating that dihydroorotate dehydrogenase is a potential differentiation regulator and a therapeutic target in acute myeloid leukemia. By screening a library of natural products, we identified a novel dihydroorotate dehydrogenase inhibitor, isobavachalcone, derived from the traditional Chinese medicine Psoralea corylifolia Using enzymatic analysis, thermal shift assay, pull down, nuclear magnetic resonance, and isothermal titration calorimetry experiments, we demonstrate that isobavachalcone inhibits human dihydroorotate dehydrogenase directly, and triggers apoptosis and differentiation of acute myeloid leukemia cells. Oral administration of isobavachalcone suppresses subcutaneous HL60 xenograft tumor growth without obvious toxicity. Importantly, our results suggest that a combination of isobavachalcone and adriamycin prolonged survival in an intravenous HL60 leukemia model. In summary, this study demonstrates that isobavachalcone triggers apoptosis and differentiation of acute myeloid leukemia cells via pharmacological inhibition of human dihydroorotate dehydrogenase, offering a potential therapeutic strategy for acute myeloid leukemia.