Cancer is the second leading cause of death in the world. The number of deaths and accidents is increasing every year. Metal-based anticancer drugs have been used clinically around the world, but they suffer from poor selectivity, serious side effects, and drug resistance. The development of drugs that target the tumor is the basis for accurate cancer treatment.
Recently, Professor Hongke Liu of Nanjing Normal University, Professor Jing Zhao and Academician Zijian Guo of Nanjing University have made breakthroughs in the development of anti-cancer drugs. They proposed a strategy of “biologically stimulated orthogonal lethality” (BCL) (Fig. 1) and published their findings in the “National Science Review” (National Science Review, NSR). The BCL strategy uses tumors as manufacturing plants to generate a highly potent Ru-rhein drug targeting tumors, which can selectively kill tumor cells and tumors in tumor-bearing mice, while there is no toxicity to normal cells. The BCL strategy generates targeted drugs from non-toxic compounds that are avoided within the tumor, not only degrading and inactivating the drug during transportation and storage, but also minimizing the dangerous side effects caused by interaction with bioactive molecules during treatment.
The copper content in cancer cells is much higher than in normal cells. Targeting drug Ru-rhein is generated from two non-toxic compounds Ru-N3 and rhein-alkyn inside the tumor with a yield of more than 80%, using copper-stimulated orthogonal biological reactions. However, the above reactions rarely occur in normal tissues. Hence tumor targeting and Ru-rhein selectivity are achieved through the BCL strategy. Ru-rhein exhibits high anticancer activity, especially towards A549 lung cancer cell, almost the same as cisplatin, while it is non-toxic to normal lung cells HLF and can be used as a candidate drug for clinical development (Fig.2). Ru-rhein targets mitochondria in cancer cells and causes autophagy cell death through the mitochondrial pathway.
A mouse model was used to validate the BCL strategy. Compared with the control group, tumor growth of the tumor-bearing mice injected with Ru-N3 and rhein-alkyn was significantly inhibited, and the other organs were virtually undamaged (Fig.3). The generality of the BCL strategy has been demonstrated in generating metallic drugs based on osmium and iridium within cancer cells.
The BCL method provides a general strategy for precisely treating diseases, and also reveals that a tumor can provide copper species that efficiently stimulate orthogonal reactions. This research was funded by the National Natural Science Foundation of China. Dr Xuling Xue, Postdoctoral Fellow at Nanjing Normal University, is the first author of this paper.
See the article:
Xuling Xue, Chenggen Qian, Qin Tao, Yuanxin Dai, Mengdi Lv, Jingwen Dong, Zhi Su, Yong Qian, Jing Zhao, Hongke Liu, Zijian Guo
Use of a biostimulated lethality strategy to generate metal-antitumor drugs that target mitochondria in vitro and in vivo
Natel Sci Rev., 2020, doi: 10.1093 / nsr / nwaa286