Most patients with pancreatic cancer were diagnosed at a late stage even with distant metastasis and died within several months. PDAC often harbors the universal mutations in the proto-oncogene K-RAS (>90% prevalence in pancreatic cancer), which persistently accelerates and activates various oncogenic events (e.g., uncontrolled proliferation, sustained angiogenesis, metastasis, or invasion), thus leading to metabolic reprogramming and resistance to cell death. Pancreatic ductal adenocarcinoma (PDAC) is the most common type of pancreatic cancer which is an extremely lethal cancer with poor prognosis and high recurrence rate. In summary, these results provide experimental evidence that DHA acts synergistically with DDP and renders PDAC cells vulnerable to ferroptosis, which may act as a promising therapeutic strategy. Moreover, pharmacologic depleting of the free iron reservoir or reconstituted expression of FTH contributes to the tolerance of DHA/DDP-induced ferroptosis, while iron addition accelerates the ferroptotic cell death. Further studies show that ferroptosis contributes to the cytotoxic effects in PDAC cells under the challenge of DHA and DDP, together with catastrophic accumulation of free iron and unrestricted lipid peroxidation. Mechanically, the combinative treatment impairs mitochondrial homeostasis, characterized by destroyed mitochondrial morphology, decreased respiratory capacity, reduced ATP production, and accumulated mitochondria-derived ROS. Combination of DHA and DDP synergistically inhibits the proliferation and induces DNA damage of PDAC cells. In the present study, we find that DHA could intensively strengthen the cytotoxicity of DDP and significantly reduce its effective concentrations both in vitro and in vivo. We and others have previously discovered that dihydroartemisinin (DHA) represents a safe and promising therapeutic agent to preferentially induce cancer cell ferroptosis. Therefore, it is imperative to develop a more effective and less toxic therapeutic strategy. However, DDP exhibits severe side-effects that can lead to discontinuation of therapy, and the acquired drug resistance of tumor cells presents serious clinical obstacles. Cisplatin (DDP) is used as a mainstay of chemotherapeutic agents in combination with other drugs or radiotherapy for PDAC therapy. Pancreatic ductal adenocarcinoma (PDAC) is an extremely lethal cancer with limited treatment options.
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