Colorectal cancer (CRC) is the third most common cancer worldwide, accounting for about 10 % of all cancer cases(Dekker et al., 2019; Patel et al., 2022). It is also the second leading cause of cancer-related death worldwide and is responsible for nearly 930,000 cancer-related deaths each year(Weitz et al., 2005). The incidence and mortality of CRC are mainly associated with aging populations and dietary habits in high-income countries(Brody, 2015). In addition, obesity, physical inactivity, and smoking, among other risk factors, also increase the risk of CRC. The ideal therapeutic targets are found in the dysregulated TGF-β/SMAD (transforming growth factor β/drosophila mothers against decapentaplegic protein), EGFR (Epidermal growth factor receptor), VEGFR/VEGRR (vascular endothelial growth factor receptor), Notch, and Hedgehog pathways, which activate the phosphatidylinositol 3-kinase/protein kinase B (PI3K/AKT) pathways(Ahmad et al., 2021). However, the complex network of downstream signaling pathways and the crosstalk between them makes it challenging to completely block specific biological interactions. Therefore, it is important to identify other target pathways for the treatment of CRC.
Ferroptosis, a form of metabolically regulated cell death, has emerged as an important pathway in cancer biology. In 2012, Dixon(Dixon et al., 2012) et al. introduced ferroptosis as an Fe2+-dependent mode of non-apoptotic cell death that is caused by Fe2+-dependent lipid peroxidation and overproduction of reactive oxygen species (ROS) (Xie et al., 2016). In recent years, accumulating evidence has suggested that the suppression of ferroptosis is linked to resistance to conventional cancer therapies and that targeting ferroptosis might provide a therapeutic potential for cancers. In fact, a recent study found that protocadherin 20 promoted ferroptosis in hepatocellular carcinoma(Jun et al., 2023).
In cancer cells, iron plays a crucial role in promoting cell growth and proliferation compared to normal cells because of the increased metabolic demands of tumor cells(Chen et al., 2023), accompanied by elevated intracellular iron concentrations(Conti et al., 2016). This phenomenon is supported by the elevated expression of ferritin (both ferritin light chain and ferritin heavy chain 1) in cancer cells(Ravet and Pilon, 2013; Tisma and Poljak-Blazi, 2011). Interestingly, previous research has shown that colorectal cancer cells are addicted to high iron levels and accumulate the metal through transferrin dependent uptake. Further, recent studies have shown that iron overload increases the sensitivity of ectopic endometrial stromal cells to ferroptosis(Luo et al., 2024). Thus, the consumption of excess Fe2+ in cancer cells could help regulate ferroptosis and could be an important therapeutic strategy for cancer treatment(Luo et al., 2024).
Iron chelators, which are natural compounds (such as siderophores) or synthetic compounds that bind to iron with a high affinity, have long been a target of interest as anticancer agents and have demonstrated antitumor efficacy against various malignancies(Eberhard et al., 2009; Jiao et al., 2009; Whitnall et al., 2006). Numerous studies have reported tumor responses following treatment with Fe2+ chelating agents(Chen et al., 2023; Fukushima et al., 2011; Sandoval-Acuña et al., 2021). Recent research has also highlighted that intracellular Fe2+ levels, encompassing potential pools of Fe2+ and the storage protein ferritin, are pivotal factors influencing chemotherapy resistance development and tumor prognosis among cancer patients(Devos et al., 2022; Feng et al., 2022; Gleason and Bush, 2021). Originally, iron chelators were first developed for use in iron overload disorders; however, their potential as anticancer agents has been gaining increasing interest. For example, deferoxamine (DFO) is a compound that is widely employed in clinical practice to alleviate Fe2+ overload conditions through its chelating action on excess free circulating Fe2+(Kontoghiorghe and Kontoghiorghes, 2016). In addition, DFO inhibits the growth of tumor cells by consuming the intracellular Fe2+ reservoir required for their enzyme activation, resulting in anticancer activity(Pei et al., 2022). Currently, DFO is widely used to treat Fe2+ overload-related diseases, such as thalassemia and tumors, and allergies or allergic reactions to DFO are rare(Sandoval-Acuña et al., 2021; Sridharan and Sivaramakrishnan, 2018). Thus, this compound also appears to have a good safety profile. However, there is not enough information on other ferroptosis-inhibiting compounds that could be used for tumor treatment.
Based on the status of previous research on the use of ferroptosis-regulating compounds for tumor treatment and the limitations in the field, in the present study, we have screened an in-house library of 700 small-molecule compounds and examined their anti-ferroptosis effect on a CRC cell line. We identified three novel meroterpene-like compounds that were able to significantly inhibit ferroptosis in the CRC cells through their action as Fe2+ chelators. These compounds may have potential as therapeutic agents for the treatment of tumors characterized by Fe2+ overload.
