Introduction
Pancreatic cancer is particularly notable for its aggressive progression and dismal prognosis, which underscores the urgent need for the development of novel therapeutic strategies that can effectively combat this formidable disease. Recent investigations have brought to light the potential of salvianolic acid B (SalB), a polyphenolic compound that is extracted from the roots of the Salvia miltiorrhiza plant, as a promising candidate for targeted cancer treatment. However, the precise mechanisms through which SalB influences metabolic changes in pancreatic cancer cells and promotes ferroptosis—a specific type of programmed cell death characterized by iron-dependent lipid peroxidation—remain to be fully elucidated. Therefore, this study aims to thoroughly investigate the impact of SalB on the metabolic reprogramming of pancreatic cancer cells, while also clarifying the specific mechanisms by which it induces ferroptosis.
Aims & Methods
We established an in situ mouse model of pancreatic cancer to evaluate SalB's anti-tumor effects at 10, 30, and 100 μM, assessing critical parameters like glutathione (GSH) levels, glutathione peroxidase 4 (GPX4) activity, malondialdehyde (MDA) production, reactive oxygen species (ROS) levels, ferrous iron (Fe2+) concentrations, mitochondrial morphology, ATP levels, enzyme activity, mitochondrial ROS, and mitochondrial membrane potential (MMP) in Panc-1, BxPC-3, and SW1990 cell lines. We also used Fer-1 to inhibit ferroptosis and reevaluated SalB's effects, exploring its relationship with ferroptosis in pancreatic cancer cells.
Results
SalB significantly reduced tumor volume in mice afflicted with in situ pancreatic cancer, all while notably not impacting the body weight of these animals, suggesting a targeted therapeutic effect without the common side effects associated with weight loss. In various cell lines, including Panc-1, BxPC-3, and SW1990, treatment with SalB resulted in a marked decline in levels of GSH and GPX4, which are crucial for cellular antioxidant defense. This decline was coupled with a significant increase in MDA and ROS, indicating that SalB effectively induces oxidative stress within the cells, a condition that can lead to cell death. Furthermore, SalB treatment led to elevated intracellular levels of Fe2+, alterations in mitochondrial morphology, a decrease in MMP, and reduced ATP levels, alongside inhibited activity of mitochondrial respiratory chain enzymes and increased production of mitochondrial ROS. These changes collectively confirm SalB's potent ability to inhibit mitochondrial function while simultaneously improving the overall metabolic condition in pancreatic cancer cells. Following pretreatment with the ferroptosis inhibitor Fer-1, the reductions in GSH, GPX4, and MMP levels, as well as the increases in MDA, ROS, and Fe2+ levels induced by SalB, were effectively reversed, demonstrating the dynamic interplay between these cellular components. Additionally, Fer-1 restored ATP levels and the diminished activity of mitochondrial respiratory chain enzymes caused by SalB treatment, while also attenuating the production of mitochondrial ROS. These findings underscore the critical role of ferroptosis in mediating the effects of SalB on mitochondrial function and highlight its significant impact on the overall metabolic state of pancreatic cancer cells, suggesting a promising avenue for therapeutic intervention.
Conclusion
SalB effectively suppresses pancreatic cancer progression by inducing ferroptosis and mitochondrial metabolic reprogramming.
References
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