Genitourinary Cancer Research Laboratory, Department of Urology, University of Washington, Seattle, WA 98195, USA.
Anticancer Drugs. 2010 Apr;21(4):423-32. doi: 10.1097/CAD.0b013e328336f57b.
Artemisinin is a plant-derived anti-malarial drug that has relatively low toxicity in humans and is activated by heme and/or intracellular iron leading to intracellular free radical formation. Interestingly, artemisinin has displayed anti-cancer activity, with artemisinin dimers being more potent than monomeric artemisinin. Intracellular iron uptake is regulated by the transferrin receptor (TfR), and the activity of artemisinin depends on the availability of iron. We examined the level of TfR in prostate cancer (PCa) tumor cells, synthesized two new artemisinin dimers, and evaluated the effect of dihydroartemisinin and artemisinin dimers, ON-2Py and 2Py, on proliferation and apoptosis in PCa cells. TfR was expressed in the majority of PCa bone and soft tissue metastases, all 24 LuCaP PCa xenografts, and PCa cell lines. After treatment with dihydroartemisinin, ON-2Py, or 2Py all PCa cell lines displayed dose-dependent decrease in cell number. 2Py was most effective in decreasing cell number. An increase in apoptotic events and growth arrest was observed in the C4-2 and LNCaP cell lines. Growth arrest was observed in PC-3 cells, but no significant change was observed in DU 145 cells. Treatment with 2Py resulted in a loss of the anti-apoptotic protein survivin in all four cell lines. 2Py treatment also decreased androgen receptor and prostate-specific antigen expression in C4-2 and LNCaP cells, with a concomitant loss of cell cycle regulatory proteins cyclin D1 and c-Myc. This study shows the potential use of artemisinin derivatives as therapeutic candidates for PCa and warrants the initiation of preclinical studies.
青蒿素是一种植物来源的抗疟药物，在人类中相对毒性较低，它通过血红素和/或细胞内铁激活，导致细胞内自由基的形成。有趣的是，青蒿素表现出抗癌活性，青蒿素二聚体比单体青蒿素更有效。细胞内铁摄取受转铁蛋白受体（TfR）调节，青蒿素的活性取决于铁的可用性。我们检查了前列腺癌（PCa）肿瘤细胞中的 TfR 水平，合成了两种新的青蒿素二聚体，并评估了二氢青蒿素和青蒿素二聚体 ON-2Py 和 2Py 对 PCa 细胞增殖和凋亡的影响。TfR 在大多数前列腺癌骨和软组织转移、所有 24 个 LuCaP PCa 异种移植瘤和 PCa 细胞系中均有表达。在用二氢青蒿素、ON-2Py 或 2Py 处理后，所有 PCa 细胞系的细胞数量均呈剂量依赖性减少。2Py 对减少细胞数量最有效。在 C4-2 和 LNCaP 细胞系中观察到凋亡事件和生长停滞的增加。在 PC-3 细胞中观察到生长停滞，但在 DU 145 细胞中未观察到明显变化。用 2Py 处理导致四种细胞系中的抗凋亡蛋白 survivin 丢失。2Py 处理还降低了 C4-2 和 LNCaP 细胞中的雄激素受体和前列腺特异性抗原表达，同时丧失了细胞周期调节蛋白 cyclin D1 和 c-Myc。这项研究表明，青蒿素衍生物有潜力作为前列腺癌的治疗候选药物，并需要开展临床前研究。
