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Redox cancer therapy The understanding of ROS mechanisms supported the development of two parallel anticancer strategies based on ROS modulation, the use of antioxidants for cancer prevention and the use of ROS inducers to exacerbate oxidative stress to lead cancer factor xa inhibitor to death [27], [133]. The second strategy represents the main mechanism of action of some current anticancer approaches, such as radio- and photodynamic therapy [134]. These therapies induce an intense and sudden burst of ROS, which cancer cells are unable to buffer, leading to cell death. Some clinically used chemotherapeutics have also been shown to induce cellular ROS. While chemotherapy-induced ROS in healthy cells have been linked to several side effects [135], [136], [137], ROS induction has been reported to occur also in cancer cells, and in some context to participate to the anticancer activity of chemotherapy [23], [24], [25]. As many cancer cells develop resistance to apoptosis, ROS eliciting this cell death pathway may not be sufficient to kill all cancer cells. The possibility of using molecules exacerbating ROS and eliciting necroptosis or ferroptosis is a promising scenario for ROS-based cancer therapies, especially for treating resistant cancers. Therefore, the list of natural and synthetic molecules with these interesting properties is increasing (Table 1).
Future directions Many questions remain unanswered regarding the role of ROS in necroptosis and ferroptosis. The context-specific involvement of mitochondrial and cytosolic ROS in necroptosis is one main research focus. Moreover, the precise final targets of ROS in both cell death forms have yet to be defined. Further research is needed to clarify the iron-dependent enzymatic activities responsible for ferroptosis. This type of cell death can also be accompanied by ER stress and eukaryotic translation initiation factor 2A (eIF2A) phosphorylation [169], which is recognized as marker of immunogenic cell death (ICD). Therefore, it would be interesting to investigate whether ferroptosis results in the release of danger associated molecular patterns, and to which extent it can eventually induce an anticancer immune response. Overall, the increasing understanding of the mechanisms underlying necroptosis and ferroptosis will benefit the advancement of redox cancer strategies and the discovery of new redox-active anticancer therapeutics.
Acknowledgements CF acknowledges support form Télévie Luxemburg. Research at LBMCC is supported by Télévie Luxembourg, the “Recherche Cancer et Sang” foundation, “Recherches Scientifiques Luxembourg” association, “Een Häerz fir Kriibskrank Kanner” association, and the Action Lions “Vaincre le Cancer”. Research at Seoul National University is supported by the Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Korea, the Tumor Microenvironment GCRC (2011-0030001) from the National Research Foundation funded by the Ministry of Science and ICT of Korea, by the Creative-Pioneering Researchers Program through Seoul National University (SNU) (Funding no. 370C-20160062). SS and MD to Brain Korea (BK) 21 Plus program, Korea.
Introduction Liver fibrosis is a growing global health problem characterized by excess deposition of fibrillar collagen, and activation of hepatic stellate cells (HSCs) [[1], [2], [3], [4]]. Strictly speaking, there are no clinical symptoms of hepatic fibrosis [[5], [6], [7]]. Its process is connected to synthesis of various cytokines and dysfunction in vivo, which gradually disrupts normal liver structure and function [[8], [9], [10]]. Without effective treatment, liver fibrosis is most likely progress to ultimately liver failure, liver cirrhosis, and even hepatocellular carcinoma [[11], [12], [13]]. Currently, treatment of hepatic fibrosis mainly focuses on removing the causes (including liver fibrosis caused by viruses, metabolism, drugs, alcohol and autoimmunity), western medicine treatment, nutritional therapy and cell regeneration therapy [[14], [15], [16], [17]]. However, these methods are either temporary palliative or too expensive for patients. Therefore, it is urgent to pursue safe, effective and affordable treatment for liver fibrosis [18]. Interestingly, Chinese medicines have been efficient in the treatment of various diseases including ischemic heart diseases [19], schizophrenia [20], chronic kidney diseases [21], liver cancer [22] and so on in recent years. Natural products from traditional Chinese medicines have made remarkable advances in the prevention and treatment of hepatic fibrosis such as puerarin [23], glycyrrhizin [24], curcumin [25] and andrographolide [26]. Hence understanding the molecular mechanisms underlying the effect of natural products-induced anti-hepatic fibrosis is especially important for developing more effective treatment strategies.