Zhang Yu, Zhang Xu, Zhou Bing
Shenzhen Institute of Synthetic Biology, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, China.
Antioxidants (Basel). 2023 Jan 22;12(2):250. doi: 10.3390/antiox12020250.
Besides the clinically proven superior antimalarial activity, artemisinins (ARTs) are also associated with anticancer properties, albeit at much lower potency. Iron and heme have been proposed as possible activators of ARTs against cancer cells. Here we show that zinc protoporphyrin-9 (ZnPPIX), a heme homolog and a natural metabolite for heme synthesis during iron insufficiency, greatly enhanced the anticancer activity of dihydroartemisinin (DHA) in multiple cell lines. Using melanoma B16 and breast cancer 4T1 cells, we demonstrated ZnPPIX dramatically elevated intracellular free heme levels, accompanied by heightened reactive oxidative species (ROS) production. The tumor-suppression activity of ZnPPIX and DHA is mitigated by antioxidant vitamin E or membrane oxidation protectant ferrostatin. In vivo xenograft animal models confirmed that ZnPPIX significantly potentiated the tumor-inhibition capability of DHA while posing no apparent toxicity to the mice. The proliferating index and growth of tumors after the combinatory treatment of DHA and ZnPPIX were evidently reduced. Considering the clinical safety profiles of both DHA and ZnPPIX, their action synergy offers a promising strategy to improve the application of ARTs in our fight against cancer.
除了临床上已证实的卓越抗疟活性外，青蒿素（ARTs）还具有抗癌特性，尽管其效力要低得多。铁和血红素被认为是青蒿素抗癌细胞的可能激活剂。在此，我们表明锌原卟啉-9（ZnPPIX），一种血红素类似物以及铁缺乏时血红素合成的天然代谢产物，能显著增强双氢青蒿素（DHA）在多种细胞系中的抗癌活性。利用黑色素瘤B16细胞和乳腺癌4T1细胞，我们证明ZnPPIX显著提高细胞内游离血红素水平，并伴随着活性氧化物质（ROS）生成增加。抗氧化剂维生素E或膜氧化保护剂铁抑素可减轻ZnPPIX和DHA的肿瘤抑制活性。体内异种移植动物模型证实，ZnPPIX显著增强DHA的肿瘤抑制能力，同时对小鼠无明显毒性。DHA和ZnPPIX联合治疗后肿瘤的增殖指数和生长明显降低。考虑到DHA和ZnPPIX的临床安全性，它们的协同作用为改善青蒿素在抗癌斗争中的应用提供了一种有前景的策略。
