A mitochondria-targeting artemisinin derivative with sharply increased antitumor but depressed anti-yeast and anti-malaria activities.
A mitochondria-targeting artemisinin derivative with sharply increased antitumor but depressed anti-yeast and anti-malaria activities.
复制标题
一种靶向线粒体的青蒿素衍生物，其抗肿瘤活性显着增强，但抗酵母菌和抗疟疾活性降低
DOI：
10.1038/srep45665
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发表时间：
2017-04-03
影响因子：
4.6
通讯作者：
Zhou B
中科院分区：
文献类型：
--
作者：
Sun C;Cao Y;Zhu P;Zhou B
有效的抗疟疾药物青蒿素还具有抗肿瘤和抑制酵母菌生长的作用。然而，青蒿素的作用机制还不是很清楚。血红素和线粒体膜可能都参与了青蒿素的作用。因为血红素也是在线粒体中合成的，所以线粒体似乎是青蒿素活性的关键细胞器。在本研究中，我们将三苯基膦(TPP)与青蒿酸(ARTA)偶联，合成了线粒体靶向青蒿素衍生物。Arta-TPP显示出比其母化合物更强的抗肿瘤活性。相比之下，Arta-TPP对酵母呼吸生长和疟疾寄生虫的活性要低得多。值得注意的是，Arta-TPP对其他类型的对照哺乳动物细胞的毒性也增加。这些结果表明青蒿素对癌细胞和疟疾或酵母细胞的作用模式不同。我们得出结论，线粒体靶向可以显著提高青蒿素的抗癌效力，但伴随而来的对正常细胞的毒性增加引起了人们的警觉。根据我们目前对青蒿素作用的理解，讨论了TPP与ARTA结合对其抗癌和抗疟疾/抗酵母菌效力的作用机制。
The potent anti-malarial drug artemisinins are additionally anti-tumorigenic and inhibitory to yeast growth. The action mechanism of artemisinins, however, is not well understood. Heme and mitochondrial membrane are both suggested to be involved in the action of artemisinins. Because heme is also synthesized in the mitochondrion, mitochondria appear to be a critical organelle for artemisinins’ activities. In this study, we synthesized a mitochondria-targeting artemisinin derivative by conjugating triphenylphosphonium (TPP) to artelinic acid (ARTa). ARTa-TPP displays far more potent anti-tumorigenic activity than its parent compound. In contrast, ARTa-TPP is much less active against yeast respiration growth and malarial parasites. Notably, ARTa-TPP is also associated with increased toxicity to other kinds of control mammalian cells. These results suggest divergent action modes for artemisinins against cancer cells and malaria or yeast cells. We conclude that mitochondrial targeting could substantially elevate the anticancer potency of artemisinins, but the accompanied increased toxicity to normal cells raises an alert. The mechanism regarding the opposing effects of TPP conjugation to ARTa on its anticancer and anti-malarial/anti-yeast potencies is discussed based on our current understandings of artemisinins’ action.