Development of Anticancer Drugs for Ferroptosis: An Analysis of Representative Natural Products

Over the past years, anticancer strategies based on ferroptosis have been well acknowledged, leading to a boom in the development of anticancer drugs at home and abroad. Natural medicines provide a direct source in the development of anti-ferroptosis drugs. Researches have suggested that many natural products have the potential for the development of ferroptosis-based anticancer drugs. Several representative ferroptosis natural anticancer drugs are listed as follows. 

1. Artemisinin

Artemisinin, a natural product of the sesquiterpenoids, is an effective ingredient in the dried stems and leaves of Artemisia annua. Nobel Prize in Physiology and Medicine was awarded to the Chinese pharmacist Tu Youyou for her discovery of artemisinin. Research findings have showed that artemisinin could exert anticancer effects by inducing iron-dependent death of tumor cells. It is revealed in mechanism studies that artemisinin binds to transferrin to enhance its selectivity and cytotoxicity to cancer cells. 

2. Dihydroartemisinin 

Dihydroartemisinin is known to be a derivative of artemisinin with high water solubility. It has been found in experiments on human liver cancer cells HepG2 that dihydroartemisinin increases the reactive oxygen species (ROS) in cancer cells through Fenton-like reaction, and reduces the expression of GSH and GPX4 to induce tumor cell ferroptosis. It was also confirmed that the exogenous nature Iron accelerated the Fenton-like reaction of dihydroartemisinin and boosted the ferroptosis of cancer cells. It has also been verified in studies that dihydroartemisinin regulates cellular iron homeostasis through ferritin regulation and iron response element signaling pathways, promotes cysteine deprivation and GPX4 inhibition, so as to sensitize cell ferroptosis. What is worth mentioning is that studies have displayed that dihydroartemisinin plays an antimalarial role by inducing ferroptosis of Plasmodium falciparum. 

3. Artesunate 

Artesunate is also regarded as a derivative of artemisinin and has significant anti-tumor activity. It has been disclosed in studies that artesunate activates lysosomes, increases the iron concentration by boosting the hydrolysis of ferritin, and then induces ferroptosis through iron dependence. It has been displayed in mechanism studies that the level of lipid peroxidation in hepatocellular carcinoma (SMMC-7721) cells increases after induced by artesunate, and the use of iron chelating agent deferoxamine eliminates the cause of artesunate lipid peroxidation in cells. 

4. Piperlongumine 

Piperlongumine is recognized as an alkaloid compound and an effective ingredient from the dried roots of Piper longum. It has been suggested in studies that piperlongumine induces ferroptosis in cancer cells by increasing the expression of reactive oxygen species (ROS) for pancreatic cancer treatment. It has been indicated in mechanism studies that the killing effect of piperlongumine is inhibited by the antioxidant N-acetylcysteine, ferroptosis inhibitors and iron chelating agents, while apoptosis inhibitors fail to inhibit its killing activity, which illustrates the anticancer effect of piperlongumine is related to ferroptosis. It has been proved in experiments on colorectal cancer cells HT29 and SW620 that piperlongumine regulates the level of reactive oxygen species (ROS), and induces ferroptosis for anticancer purpose by controlling the expression of GSH and Nrf2.

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Over the past years, ferroptosis has turned into a hot topic in drug research and development. It also exhibits the potential for targeted drug development in inflammation, infection, stroke, non-alcoholic steatohepatitis and many other diseases, in addition to cancer treatment. For example, studies have shown that Tanshinone IIA inhibits ROS, lipid peroxide activity and iron content in mouse hippocampal cells, and further inhibits the occurrence of ferroptosis to protect hippocampal cells. This indicates ginshinone IIA's potential in development of anti-ferroptosis therapeutic drugs in neurological diseases. Ferroptosis is an emerging field of drug development and will inevitably take a bigger part in the treatment of diseases in the future along with the continuous deepening of research. Meanwhile, natural products are accepted as an important source of drug development, and their dominance role will necessarily show in drug development. In the years to come, more and more anti-ferroptosis natural medicines will be developed to favor more patients. 

References: 

1.Research Progress of Chinese Medicine on the Mechanism of Ferroptosis，2021；

2.Ｒesearch Status of Ferroptosis and Inflammatory Diseases，2021；

3.Mechanisms of ferroptosis and its involvement in hepatocellular carcinoma，2020.