隨著我國科學家憑借對青蒿素類藥物的研究獲得2011年國際拉斯科臨床醫(yī)學大獎,，青蒿素及其衍生物再度成為舉世矚目的明星分子,，其中雙氫青蒿素（DHA）是青蒿素的主要代謝產(chǎn)物和活性最強的一種衍生物。近年來,，王慧研究組對青蒿素類化合物的抗腫瘤功能及機制開展了多項研究,，已發(fā)現(xiàn)青蒿素及其衍生物對卵巢癌、肝癌的抗癌效果并探討了其作用機制,。本研究中,，該組巴乾等研究人員發(fā)現(xiàn)，DHA能造成腫瘤細胞鐵元素的缺乏,、降低鐵元素的吸收,、干擾細胞內(nèi)鐵元素既有的平衡狀態(tài)，且這種改變與氧化損傷無關,。進一步研究發(fā)現(xiàn),，DHA可以降低細胞膜上的轉鐵蛋白受體1（TfR1）水平，通過脂筏介導的內(nèi)吞作用對其進行調(diào)控,，減弱了細胞對鐵的吸收從而殺傷腫瘤細胞,。該研究結果將為青蒿素類以及鐵元素靶向類抗腫瘤藥物的開發(fā)提供理論基礎。
該研究課題得到了國家自然科學基金委,、中國科學院和上海市科委的資助,。（生物谷Bioon.com）
doi:10.1371/journal.pone.0042703
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Dihydroartemisinin Exerts Its Anticancer Activity through Depleting Cellular Iron via Transferrin Receptor-1
Qian Ba, Naiyuan Zhou, Juan Duan, Tao Chen, Miao Hao, Xinying Yang, Junyang Li, Jun Yin, Ruiai Chu, Hui Wang
Artemisinin and its main active metabolite dihydroartemisinin, clinically used antimalarial agents with low host toxicity, have recently shown potent anticancer activities in a variety of human cancer models. Although iron mediated oxidative damage is involved, the mechanisms underlying these activities remain unclear. In the current study, we found that dihydroartemisinin caused cellular iron depletion in time- and concentration-dependent manners. It decreased iron uptake and disturbed iron homeostasis in cancer cells, which were independent of oxidative damage. Moreover, dihydroartemisinin reduced the level of transferrin receptor-1 associated with cell membrane. The regulation of dihydroartemisinin to transferrin receptor-1 could be reversed by nystatin, a cholesterol-sequestering agent but not the inhibitor of clathrin-dependent endocytosis. Dihydroartemisinin also induced transferrin receptor-1 palmitoylation and colocalization with caveolin-1, suggesting a lipid rafts mediated internalization pathway was involved in the process. Also, nystatin reversed the influences of dihydroartemisinin on cell cycle and apoptosis related genes and the siRNA induced downregulation of transferrin receptor-1 decreased the sensitivity to dihydroartemisinin efficiently in the cells. These results indicate that dihydroartemisinin can counteract cancer through regulating cell-surface transferrin receptor-1 in a non-classical endocytic pathway, which may be a new action mechanism of DHA independently of oxidative damage.
