Guangdong Provincial Key Laboratory of Tumor Immunotherapy, Cancer Research Institute, School of Basic Medical Sciences, Southern Medical University, Guangzhou, 510515, China.
Center for Regenerative and Translational Medicine, Guangdong Provincial Academy of Chinese Medical Sciences, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, 510632, China.
Oncogene. 2018 Sep;37(37):5079-5087. doi: 10.1038/s41388-018-0331-z. Epub 2018 May 24.
Cancer chemotherapeutic agents such as doxorubicin are DNA damage inducers that also kill normal cells, making them highly toxic to cancer patients. To improve the efficacy and safety of chemotherapy, it is important to develop new chemotherapeutic agents that selectively kill cancer cells. Here we demonstrate that artemisitene (ATT), a natural derivative of the antimalarial drug artemisinin, selectively induces DNA double-stranded breaks (DSBs) and apoptosis in various human cancer cells by suppressing the expression of topoisomerases in human cancer cells. ATT effectively kills human cancer cells without apparent cytotoxicity on normal human cells or mouse liver and kidney. We discovered that c-Myc induces the expression of topoisomerases to prevent accumulation of DNA damage in human cancer cells. ATT selectively destabilizes c-Myc in human cancer cells by promoting the ubiquitination of c-Myc through the specific induction of the c-Myc E3 ligase NEDD4. Therefore, ATT represents a promising new chemotherapeutic drug candidate that can eliminate human cancer cells with minimized cytotoxic effects on normal cells.
癌症化疗药物，如阿霉素，是诱导 DNA 损伤的物质，同时也会杀死正常细胞，对癌症患者具有高度毒性。为了提高化疗的疗效和安全性，开发选择性杀伤癌细胞的新化疗药物非常重要。在这里，我们证明了青蒿素（ART），一种抗疟药物青蒿素的天然衍生物，通过抑制人癌细胞中端粒酶的表达，选择性地诱导各种人癌细胞中的 DNA 双链断裂（DSB）和细胞凋亡。ART 能有效地杀死人癌细胞，而对正常的人细胞或小鼠的肝和肾没有明显的细胞毒性。我们发现 c-Myc 诱导端粒酶的表达，以防止人癌细胞中 DNA 损伤的积累。ART 通过特异性诱导 c-Myc E3 连接酶 NEDD4 促进 c-Myc 的泛素化，从而选择性地使 c-Myc 在人癌细胞中不稳定。因此，ART 代表了一种有前途的新的化疗药物候选物，它可以消除人癌细胞，而对正常细胞的细胞毒性最小化。
