Heme mediates cytotoxicity from artemisinin and serves as a general anti-proliferation target.
Heme mediates cytotoxicity from artemisinin and serves as a general anti-proliferation target.
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DOI：
10.1371/journal.pone.0007472
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发表时间：
2009-10-28
期刊：
影响因子：
3.7
通讯作者：
Gerhard GS
中科院分区：
文献类型：
--
作者：
Zhang S;Gerhard GS
血红素(Fe2+原卟啉IX)是一种重要的分子，青蒿素及其衍生物具有很强的抗疟疾作用，但其来源和性质仍存在争议。青蒿素在体外和体内也表现出对癌细胞的选择性细胞毒作用。我们证明细胞内的血红素是青蒿素细胞毒作用的生理相关的介体。通过加入氨基乙酰丙酸、原卟啉IX或转铁蛋白结合铁来增加细胞内血红素的合成增加了双氢青蒿素的细胞毒性，而通过加入琥珀酰丙酮来减少血红素的合成则降低了它的细胞毒活性。建立了一种简单、可靠的高通量分析方法，用于筛选能够与血红素相互作用的化合物。对天然产物文库进行了筛选，除青蒿素外，还鉴定了化合物Coralyne是一种与血红素相互作用的化合物，具有依赖于血红素合成的细胞毒活性。这些结果表明，细胞血红素可能是抗寄生虫和抗癌治疗药物开发的一般靶点。
Heme (Fe2+ protoporphyrin IX) is an essential molecule that has been implicated the potent antimalarial action of artemisinin and its derivatives, although the source and nature of the heme remain controversial. Artemisinins also exhibit selective cytotoxicity against cancer cells in vitro and in vivo. We demonstrate that intracellular heme is the physiologically relevant mediator of the cytotoxic effects of artemisinins. Increasing intracellular heme synthesis through the addition of aminolevulinic acid, protoporphyrin IX, or transferrin-bound iron increased the cytotoxicity of dihydroartemisinin, while decreasing heme synthesis through the addition of succinyl acetone decreased its cytotoxic activity. A simple and robust high throughput assay was developed to screen chemical compounds that were capable of interacting with heme. A natural products library was screened which identified the compound coralyne, in addition to artemisinin, as a heme interacting compound with heme synthesis dependent cytotoxic activity. These results indicate that cellular heme may serve a general target for the development of both anti-parasitic and anti-cancer therapeutics.
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