Ruscogenin induces ferroptosis in pancreatic cancer cells

Abstract

Pancreatic cancer is characterized by aggressive and highly metastatic phenotypes. This disease exhibits a poor patient prognosis and is considered a challenge due to the limited treatment options encountered in clinical practice. Previous studies have shown that ruscogenin, a saponin found in the root of Ophiopogon japonicus, exerts a wide range of biological functions including anticancer activity. In the present study, the effects of ruscogenin were investigated on pancreatic cancer cells and the potential molecular mechanism of this compound was explored. Cell viability was assessed using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Cell death was measured by trypan blue staining and by flow cytometry. The number of iron oxide nanoparticles was measured using Prussian blue staining. Reactive oxygen species (ROS) production was assessed using flow cytometry with dihydroethidium staining. Protein expression of the associated genes was assayed by western blotting. Furthermore, in vivo experiments were conducted to confirm the antitumor effects and assay the potential toxicity of ruscogenin in a nude mouse xenograft model. The results indicated that ruscogenin significantly repressed cell viability and induced cell death of pancreatic cancer cells in vitro in a dose-and time-dependent manner. Furthermore, ruscogenin increased the concentration of intracellular ferrous irons and the production of ROS. This effect was inhibited by deferoxamine (DFO). Ruscogenin induced ferroptosis by regulating the levels of transferrin and ferroportin. These two proteins were involved in ruscogenin-induced pancreatic cancer cell death. Finally, in vivo experiments demonstrated the antitumor effect of ruscogenin on pancreatic cancer xenografts in the absence of apparent toxicity. Taken collectively, the data demonstrated that ruscogenin exhibited anticancer effects in pancreatic cancer cells by inducing ferroptosis. The findings suggested that this compound may be further developed as a promising anticancer candidate for the treatment of pancreatic cancer.

The construction and analysis of a ferroptosis-related gene prognostic signature for pancreatic cancer

“…ARF6 can mitigate gemcitabine resistance by conferring PCa cells the sensitivity to RSL3-induced ferroptosis [ 34 ]. Studies have demonstrated that multiple chemical extracts can promote the death of pancreatic cancer cells mainly through the induction of ferroptosis [ 17 , 35 , 36 ]. Ferroptosis induced by SLC7A11 deletion has be verified to slow down the growth of the xenograft derived from PCa [ 37 ].…”

Ferroptosis: Biochemistry and Biology in Cancers

“…Many extracts from plants and herbs also exhibit anti-tumor effects by inducing ferroptosis. Ruscogenin can induce ferroptosis by improving ROS generation and trigger intracellular iron accumulation by upregulating transferrin and downregulating FPN ( 49 ). Piperlongumine can also induce ferroptosis in pancreatic cancer cells ( 171 ).…”

A Promising Future of Ferroptosis in Tumor Therapy

“…Moreover, the combination of ART and GRP78 inhibitor worked in KRAS mutant PDAC ( Wang et al, 2019 ). Ruscogenin can also induce ferroptosis by influencing the levels of ferroportin and transferrin to exhibit anticancer effects ( Song et al, 2020 ). Yamaguchi et al (2018) demonstrated triple combined treatment using Cotylenin A, Piperlongumine, and sulfasalazine as a successful therapeutic method against PDAC.…”

“…Moreover, it is time- and dose-dependent. Furthermore, in BxPC-3 human pancreatic cancer xenografts, there are significant antitumor effects without any toxicity detected in normal tissues ( Song et al, 2020 ).…”