TG003 Introduction Globally lung cancer has the highest
Globally, lung cancer has the highest morbidity and mortality rates of all types of cancer, with 1.5 million patients newly diagnosed annually . Approximately 85% of lung cancer cases are non-small cell lung cancer (NSCLC) . The first-line treatment for NSCLC is surgical resection combined with radiotherapy and chemotherapy [1,3]. Despite significant improvements in the efficacy of chemotherapy drugs and the availability of molecularly targeted therapy drugs in clinical practice in the past decade, the 5-year survival rate of patients with NSCLC is still low [1,3]. Tumor metastasis is a critical factor in the low survival rate for patients with NSCLC, which is associated with a variety of factors, including angiogenesis [4,5], epithelial-mesenchymal transition (EMT) [, , ], and the migration  and invasion [10,11] of tumor cells. The activation of the CXCR4/SDF1 axis plays an important role in the process of NSCLC metastasis [, , ].
Despite the development of small-molecule drugs with greater specificity and efficacy against tumors, the side effects of chemotherapy drugs are severe, limiting their clinical application. Natural plant extracts from a wide range of sources may have fewer side effects and higher tolerability and have provided novel insights into cancer treatment in recent years . Hesperidin is a natural flavonoid glycoside compound, occurring in orange peel and other citrus species, that is widely used in Chinese herbal medicine . It was previously demonstrated to induce anticancer activity through the promotion of apoptosis [, , , , ]. Furthermore, hesperidin affected the expression of MMP family members and EMT-related proteins to inhibit cell invasion, resulting in anti-cancer activity [, , ]. In vitro and in vivo studies have demonstrated that hesperidin enhances antioxidant activity, thus inhibiting tumor development [25,26]. Our previous studies have identified that hesperidin promotes the apoptosis of A549 NSCLC TG003 by regulating the proteins in the mitochondrial apoptosis pathway and modulating the expression of cell cycle-related molecules, without any negative effects on BEAS-2B human normal lung epithelial cells . However, data regarding the effect of hesperidin on NSCLC cells is incomplete. Hence, we investigated the SDF-1/CXCR-4 signaling pathway and EMT process to understand the underlying mechanisms of the effect of hesperidin. The reported results may provide the foundation for the development of hesperidin as a safer and more effective anticancer drug for NSCLC.
Materials and methods
Discussion Cell migration is a normal physiological process, required for chemotaxis of white blood cells and directional movement of cells from other tissues [27,28]. However, in tumor tissue, the metastatic ability of malignant tumor cells is significantly associated with the likelihood of patient death . Previous studies have shown that the activation of tumor cell migration is associated with the activity of the SDF-1/CXCR-4 signaling pathway [, , ]. The SDF-1-activated CXCR-4 receptor, which is folded and delivered to the cell surface by HSP90, induces a phosphorylation cascade, leading to actin reorganization and subsequent cell migration . In the present study, we report that the SDF-1α-mediated enhancement of migratory ability in A549 cells could be inhibited by treatment with the SDF-1/CXCR-4 specific inhibitor AMD3100 or hesperidin. Based on the results of ELISA and western blotting, we confirmed that hesperidin could significantly reduce the protein expression of CXCR-4 and the level of SDF-1 secreted from A549 cells. Thus, hesperidin may potentially inhibit tumor cell metastasis through a complicated process. Interestingly, a recent study by Li et al. found that the natural product Kongensin A was a non-canonical HSP90 inhibitor that blocked RIP3-dependent necroptosis, providing a new perspective on the matter . This informed our hypothesis that the inhibitory effect of hesperidin on the migratory and invasive capabilities of human NSCLC cells may be mediated by the regulation of SDF-1 and downstream molecule expression and activity, through target proteins such as HSP90, although further study is required prior to the development of hesperidin as a therapeutic drug.