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首页> 外文期刊>Cell discovery. >Dihydroartemisinin selectively inhibits PDGFRα-positive ovarian cancer growth and metastasis through inducing degradation of PDGFRα protein
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Dihydroartemisinin selectively inhibits PDGFRα-positive ovarian cancer growth and metastasis through inducing degradation of PDGFRα protein

机译：双氢青蒿素通过诱导PDGFRα蛋白降解来选择性抑制PDGFRα阳性卵巢癌的生长和转移

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To develop traditional medicines as modern pharmacotherapies, understanding their molecular mechanisms of action can be very helpful. We have recently reported that Artemisinin and its derivatives, which are clinically used anti-malarial drugs, have significant effects against ovarian cancer, but the direct molecular targets and related combination?therapy have been unclear. Herein, we report that dihydroartemisinin, one of the most active derivatives of Artemisinin, directly targets platelet-derived growth factor receptor-alpha (PDGFRα) to inhibit ovarian cancer cell growth and metastasis. Dihydroartemisinin directly binds to the intercellular domain of PDGFRα, reducing its protein stability by accelerating its ubiquitin-mediated degradation, which further inactivates downstream phosphoinositide 3-Kinase and mitogen-activated protein kinase pathways and subsequently represses epithelial–mesenchymal transition, inhibiting cell growth and metastasis of PDGFRα-positive ovarian cancer in vitro and in vivo . A combinational treatment reveals that dihydroartemisinin sensitizes ovarian cancer cells to PDGFR inhibitors. Our clinical study also finds that PDGFRα is overexpressed and positively correlated with high grade and metastasis in human ovarian cancer. Considering that Artemisinin compounds are currently clinically used drugs with favorable safety profiles, the results from this study will potentiate their use in combination with clinically used PDGFRα inhibitors, leading to maximal therapeutic efficacy with minimal adverse effects in PDGFRα-positive cancer patients. These findings also shed high light on future development of novel Artemisinin-based targeted therapy.
机译：要将传统药物发展为现代药物疗法，了解它们的分子作用机理可能非常有帮助。我们最近报道，临床上使用的抗疟疾药物青蒿素及其衍生物对卵巢癌有显着作用，但是尚不清楚直接的分子靶标和相关的联合疗法。在本文中，我们报道了双氢青蒿素，青蒿素的最活跃衍生物之一，直接靶向血小板衍生的生长因子受体-α（PDGFRα），以抑制卵巢癌细胞的生长和转移。双氢青蒿素直接结合至PDGFRα的细胞间结构域，通过加速其泛素介导的降解而降低其蛋白质稳定性，从而进一步失活下游的磷酸肌醇3-激酶和有丝分裂原激活的蛋白激酶途径，并随后抑制上皮-间质转化，抑制细胞生长和转移PDGFRα阳性卵巢癌的体内外实验研究。联合治疗表明，双氢青蒿素可使卵巢癌细胞对PDGFR抑制剂敏感。我们的临床研究还发现，PDGFRα在人类卵巢癌中过度表达且与高级别和转移呈正相关。考虑到青蒿素化合物目前是临床上使用的药物，具有良好的安全性，这项研究的结果将加强其与临床上使用的PDGFRα抑制剂的组合使用，从而在PDGFRα阳性癌症患者中获得最大的治疗效果和最小的不良反应。这些发现也为基于青蒿素的新型靶向治疗的未来发展提供了亮点。

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