Abstract
Cucurbitacin B (CuB) is a widely available triterpenoid molecule that exhibits various biological activities. Previous studies on the anti-tumour mechanism of CuB have mostly focused on cell apoptosis, and research on the ferroptosis-inducing effect has rarely been reported. Herein, we first discovered the excellent cytotoxicity of CuB towards human nasopharyngeal carcinoma cells and elucidated its potential ferroptosis-inducing mechanisms. Morphology alterations of mitochondrial ultrastructure, as observed via transmission electron microscopy, showed that CuB-treated cells undergo ferroptosis. CuB caused intracellular accumulation of iron ions and depletion of glutathione. Detailed molecular mechanism investigation confirmed that CuB both induced widespread lipid peroxidation and downregulated the expression of GPX4, ultimately initiating a multipronged mechanism of ferroptosis. Furthermore, CuB exhibited anti-tumour effects in vitro by inhibiting cellular microtubule polymerization, arresting cell cycle and suppressing migration and invasion. Finally, CuB significantly inhibited tumour progression without causing obvious side effects in vivo. Altogether, our study highlighted the therapeutic potential of CuB as a ferroptosis-inducing agent for nasopharyngeal cancer, and it provided valuable insights for developing effective anti-tumour agents with novel molecular mechanisms derived from natural products.
Highlights
Natural products have been the main source of biologically active substances, especially antitumour lead compounds with minimal side effects
Compared with the other cancer cell lines, the nasopharyngeal carcinoma cell line CNE1 was most sensitive to Cucurbitacin B (CuB) (IC50 = 16 nM) after exposure for 48 h (Table 1)
An annexin V/propidium iodide (PI) staining assay was firstly performed to investigate whether cell death occurs through apoptosis in CNE1 cells
Summary
Natural products have been the main source of biologically active substances, especially antitumour lead compounds with minimal side effects. The cucurbitacins are a group of tetracyclic triterpenoid natural products derived from oriental herbs that show anti-tumour activity against various human cancers. Cucurbitacin B (CuB, Fig. 1), isolated from Trichosanthes kirilowii Maximowicz, was one of the most abundant and Canonical caspase-dependent apoptosis has long been recognized as the major mechanism of anti-tumour natural products. An increasing number of other novel mechanisms of cell death have recently been identified. These detailed mechanism studies validated the ferroptosis-inducing effect of CuB, verifying a novel non-apoptosis cell death in nasopharyngeal cancer cells. The in vitro and in vivo anti-tumour effect of CuB indicated the potential of CuB as a promising naturally derived ferroptosisinducing agent and ferroptosis-based cancer therapy
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