{"title":"Schizandrin A enhances the sensitivity of gastric cancer cells to 5-FU by promoting ferroptosis","authors":"","doi":"10.1007/s10616-024-00623-4","DOIUrl":null,"url":null,"abstract":"<h3>Abstract</h3> <p>Schizandrin A (Sch A) exert anticancer and multidrug resistance-reversing effects in a variety of tumors, but its effect on 5-fluorouracil (5-Fu) in gastric cancer (GC) cells remains unclear. The aim of the present study was to examine the resistance-reversing effect of Schizandrin A and assess its mechanisms in 5-Fu-resistant GC cells.5-Fu-sensitive GC cells were treated with 5-Fu and 5-Fu-resistant GC cells AGS/5-Fu and SGC7901/5-Fu were were established. These cells were stimulated with Schizandrin A alone or co-treated with 5-Fu and their effect on tumor cell growth, proliferation, migration, invasion and ferroptosis-related metabolism were investigated both in vitro and in vivo. A number of additional experiments were conducted in an attempt to elucidate the molecular mechanism of increased ferroptosis. The results of our study suggest that Schizandrin A in combination with 5-Fu might be useful in treating GC by reverse drug resistance. It was shown that Schizandrin A coadministration suppressed metastasis and chemotherapy resistance in 5-Fu-resistant GC cells through facilitating the onset of ferroptosis, which is an iron-dependent form of cell death, which was further demonstrated in a xenograft nude mouse model. Mechanistically, Schizandrin A co-administration synergistically increased the expression of transferin receptor, thus iron accumulates within cells, leading to lipid peroxidation, which ultimately results in 5-Fu-resistant GC cells death. The results of this study have provided a novel strategy for increasing GC chemosensitivity, indicating Schizandrin A as a novel ferroptosis regulator. Mechanistically, ferroptosis is induced by Schizandrin A coadministration via increasing transferrin receptor expression.</p>","PeriodicalId":2,"journal":{"name":"ACS Applied Bio Materials","volume":null,"pages":null},"PeriodicalIF":4.6000,"publicationDate":"2024-03-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"ACS Applied Bio Materials","FirstCategoryId":"99","ListUrlMain":"https://doi.org/10.1007/s10616-024-00623-4","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"MATERIALS SCIENCE, BIOMATERIALS","Score":null,"Total":0}
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Abstract
Schizandrin A (Sch A) exert anticancer and multidrug resistance-reversing effects in a variety of tumors, but its effect on 5-fluorouracil (5-Fu) in gastric cancer (GC) cells remains unclear. The aim of the present study was to examine the resistance-reversing effect of Schizandrin A and assess its mechanisms in 5-Fu-resistant GC cells.5-Fu-sensitive GC cells were treated with 5-Fu and 5-Fu-resistant GC cells AGS/5-Fu and SGC7901/5-Fu were were established. These cells were stimulated with Schizandrin A alone or co-treated with 5-Fu and their effect on tumor cell growth, proliferation, migration, invasion and ferroptosis-related metabolism were investigated both in vitro and in vivo. A number of additional experiments were conducted in an attempt to elucidate the molecular mechanism of increased ferroptosis. The results of our study suggest that Schizandrin A in combination with 5-Fu might be useful in treating GC by reverse drug resistance. It was shown that Schizandrin A coadministration suppressed metastasis and chemotherapy resistance in 5-Fu-resistant GC cells through facilitating the onset of ferroptosis, which is an iron-dependent form of cell death, which was further demonstrated in a xenograft nude mouse model. Mechanistically, Schizandrin A co-administration synergistically increased the expression of transferin receptor, thus iron accumulates within cells, leading to lipid peroxidation, which ultimately results in 5-Fu-resistant GC cells death. The results of this study have provided a novel strategy for increasing GC chemosensitivity, indicating Schizandrin A as a novel ferroptosis regulator. Mechanistically, ferroptosis is induced by Schizandrin A coadministration via increasing transferrin receptor expression.
摘要 五味子甲素（Sch A）在多种肿瘤中具有抗癌和多药耐药性逆转作用，但其对胃癌（GC）细胞中5-氟尿嘧啶（5-Fu）的作用仍不清楚。本研究的目的是研究五味子甲素的耐药性逆转作用，并评估其在对5-Fu耐药的胃癌细胞中的作用机制。这些细胞单独或与 5-Fu 联合处理后都会受到五味子素 A 的刺激，并在体外和体内研究了它们对肿瘤细胞生长、增殖、迁移、侵袭和铁蛋白相关代谢的影响。我们还进行了其他一些实验，试图阐明铁突变增加的分子机制。我们的研究结果表明，五味子素 A 与 5-Fu 联用可能有助于通过逆转耐药性来治疗 GC。在异种移植裸鼠模型中，研究进一步证实了五味子异黄酮 A 通过促进铁素沉着（一种铁依赖性细胞死亡形式）的发生，抑制了对 5-Fu 耐药的 GC 细胞的转移和化疗耐药性。从机理上讲，同时服用五味子异黄酮 A 可协同增加转移素受体的表达，从而使铁在细胞内蓄积，导致脂质过氧化，最终导致耐 5-Fu 的 GC 细胞死亡。这项研究的结果提供了一种提高 GC 化疗敏感性的新策略，表明五味子异黄酮 A 是一种新型的铁突变调节剂。从机理上讲，五味子异黄酮 A 可通过增加转铁蛋白受体的表达来诱导铁变态反应。
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