|Table of Contents|

Catechin enhanced the killing effects of 5-FU on gastric cancer cells through promoting ferroptosis of gastric cancer cells

Journal Of Modern Oncology[ISSN:1672-4992/CN:61-1415/R]

Issue:
2024 16
Page:
2981-2989
Research Field:
Publishing date:

Info

Title:
Catechin enhanced the killing effects of 5-FU on gastric cancer cells through promoting ferroptosis of gastric cancer cells
Author(s):
XU Tao1; JING Wenjun2; LIU Jing1
1.Instrumental Analysis Center of QAU,Shandong Qingdao 266109,China;2.Department of Oncology,Qingdao Central Hospital,Qingdao University，Shandong Qingdao 266042,China.
Keywords:
catechin; 5-FU; ferroptosis; Fe2+; Hmox1
PACS:
R735.2
DOI:
10.3969/j.issn.1672-4992.2024.16.009
Abstract:
Objective:To investigate the effects and mechanisms of catechin on the chemotherapy of gastric cancer.Methods:Gastric cancer cells (AGS and GC7901) were treated with 5-FU (100 μg/mL) for 0 h,3 h,6 h,9 h,12 h,16 h,24 h separately.PI staining and flow cytometry were used to detect cell deaths of gastric cancer cells.Western Blot assays were performed to detect expression levels of ferroptosis-associated signature proteins glutathione peroxidase 4 (GPX4),solute carrier family 7 member 11 (SLC7A11),and ferritin heavy polypeptide (FTH) in gastric epithelial cells (RGM-1) and gastric cancer cells (AGS and GC7901).The gray-scale values were evaluated by Image J.Gastric cancer cells were divided into 4 groups:Control group,5-FU treatment group,5-FU treatment combined with catechin treatment group,and 5-FU treatment combined with DMSO treatment.Cell deaths were detected by PI staining and flow cytometry.Lipid peroxides accumulation was detected by C11-BODIPY581/591 staining and flow cytometry.Ferroptosis-associated signature proteins were detected by Western Blot assays.The free Fe2+ levels were detected by absorption spectrophotometry.The free Fe2+ levels were detected in the isolated mitochondria and cytoplasm respectively and the intracellular localization of the increased Fe2+ were detected by Mito-Ferro Green staining and fluorescence microscopy.The expression levels of Hmox1 were detected in each group by Western Blot assays and the gray-scale values were evaluated by Image J.Gastric cancer cells were divided into 5 groups:Control group,5-FU treatment group,5-FU treatment combined with catechin treatment group,5-FU treatment combined with catechin and siRNA-NC group，5-FU treatment combined with catechin and siRNA-Hmox1 group.Fe2+ levels in mitochondria,lipid peroxides accumulation and cell deaths were detected respectively in each group.Results:Cell deaths of gastric cancer cells increased when underwent 5-FU treatment within 12 h.However,the percentage of cell deaths did not increase obviously within 5-FU treatment from 12 h to 24 h,showing drug resistance to 5-FU.The expression levels of ferroptosis-associated signature proteins GPX4,SLC7A11 and FTH in cancer cells were significantly higher than that in normal gastric mucosal epithelial cells (P<0.05).Cell death and lipid peroxides accumulation in 5-FU combined with catechin treatment group were significantly higher than those in the control group (P<0.05),while the expression levels of ferroptosis-associated signature proteins GPX4,SLC7A11 and FTH were significantly decreased in the 5-FU treatment combined with catechin treatment group (P<0.05).The free Fe2+ levels in the cytoplasm were not changed while the free Fe2+ levels in the mitochondria were significantly higher in the 5-FU treatment combined with catechin treatment group than those in the control group (P<0.05).The expression levels of Hmox1 protein in the 5-FU treatment combined with catechin treatment group were significantly higher than that in the control group (P<0.05).Compared with the 5-FU combined with catechin and siRNA-NC treatment group,the free Fe2+ levels in the mitochondria,the lipid peroxidation accumulation and the cell deaths were significantly decreased in the 5-FU combined with catechin and siRNA-Hmox1 treatment group (P<0.05).Conclusion:Catechin enhanced the killing effects of 5-FU on gastric cancer cells by promoting the expression levels of Hmox1,which increased mitochondrial Fe2+ levels and induced ferroptosis.

References:

［1］ ZONG L,ABE M,SETO Y,et al.The challenge of screening for early gastric cancer in China［J］.Lancet,2016,388(10060):2606.
［2］ SETHY C,KUNDU CN.5-fluorouracil (5-FU) resistance and the new strategy to enhance the sensitivity against cancer:Implication of DNA repair inhibition［J］.Biomed Pharmacother,2021,137:111285.
［3］张岩，田素礼，周勇旭，等.SLC6A9对结直肠癌细胞生长和对5-FU药物敏感性的影响［J］.现代肿瘤医学，2024,32(7):1236-1241. ZHANG Y,TIAN SL,ZHOU YX,et al.Effects of SLC6A9 on the growth of colorectal cancer cells and the sensitivity to 5-FU［J］.Modern Oncology,2024,32(7):1236-1241.
［4］ DIXON SJ,LEMBERG KM,LAMPRECHT MR,et al.Ferroptosis:An iron-dependent form of nonapoptotic cell death［J］.Cell,2012,149(5):1060-1072.
［5］ XU T,DING W,JI XY,et al.Molecular mechanisms of ferroptosis and its role in cancer therapy［J］.J Cell Mol Med,2019,23(8):4900-4912.
［6］ BARANWAL A,AGGARWAL P,RAI A,et al.Pharmacological actions and underlying mechanisms of catechin:A review［J］.Mini-Rev Med Chem,2022,22(5):821-833.
［7］ YANG CS,WANG H,SHERIDAN ZP.Studies on prevention of obesity,metabolic syndrome,diabetes,cardiovascular diseases and cancer by tea［J］.J Food Drug Anal,2018,26(1):1-13.
［8］ MISHRA CB,PANDEY P,SHARMA RD,et al.Identifying the natural polyphenol catechin as a multi-targeted agent against SARS-CoV-2 for the plausible therapy of COVID-19:an integrated computational approach［J］.Brief Bioinform,2021,22(2):1346-1360.
［9］ FANG XX,WANG H,HAN D,et al.Ferroptosis as a target for protection against cardiomyopathy［J］.Proc Natl Acad Sci USA,2019,116(7):2672-2680.
［10］ PRZYSTUPSKI D,MICHEL O,ROSSOWSKA J,et al.The modulatory effect of green tea catechin on drug resistance in human ovarian cancer cells［J］.Med Chem Res,2019,28(5):657-667.
［11］ ZHOU M,DONG J,HUANG J,et al.Chitosan-gelatin-EGCG nanoparticle-meditated LncRNA TMEM44-AS1 silencing to activate the P53 signaling pathway for the synergistic reversal of 5-FU resistance in gastric cancer［J］.Adv Sci,2022,9(22):e2105077.
［12］ CASTELLI V,GIORDANO A,BENEDETTI E,et al.The great escape:The power of cancer stem cells to evade programmed cell death［J］.Cancers,2021,13(2):328.
［13］ GUO HX,WANG Q,WANG C,et al.Secular trends in gastric and esophageal cancer attributable to dietary carcinogens from 1990 to 2019 and projections until 2044 in China:Population-based study［J］.Jmir Public Hlth Sur,2023,9:e48449.
［14］ CHEN Z,LI Y,TAN B,et al.Progress and current status of molecule-targeted therapy and drug resistance in gastric cancer［J］.Drug Today,2020,56(7):469-482.
［15］ YANG C,SONG J,HWANG S,et al.Apigenin enhances apoptosis induction by 5-fluorouracil through regulation of thymidylate synthase in colorectal cancer cells［J］.Redox Biol,2021,47:102144.
［16］ RHO S,WANG C,HOSSEINI DEHKORDI SH,et al.Bleeding and thrombotic events in bevacizumab-treated patients with colorectal cancer on novel oral anticoagulants and antiplatelet medications［J］.Am Heart J Plus,2023,27:100283.
［17］ YUAN J,KHAN SU,YAN J,et al.Baicalin enhances the efficacy of 5-fluorouracil in gastric cancer by promoting ROS-mediated ferroptosis［J］.Biomed Pharmacother,2023,164:114986.
［18］ PARK SM,KIM DY,LEE KH,et al.Anti-tumor efficacy of oleuropein-loaded ZnO/Au mesoporous silica nanoparticle in 5-FU-resistant colorectal cancer cells［J］.Int J Nanomedicine,2024,19:2675-2690.
［19］ HONG G,WU H,MA ST,et al.Catechins from oolong tea improve uterine defects by inhibiting STAT3 signaling in polycystic ovary syndrome mice［J］.Chin Med,2020,15(1):125.
［20］ LEI P,CAO L,ZHANG H,et al.Polyene phosphatidylcholine enhances the therapeutic response of oxaliplatin in gastric cancer through Nrf2/HMOX1 mediated ferroptosis［J］.Transl Oncol,2024,43:101911.

Memo

Memo:
National Natural Science Foundation of China(No.82000290）；国家自然科学基金资助项目(编号：82000290)；青岛农业大学高层次人才启动基金资助项目(编号:663/1120108，663/1121022)
Last Update: 1900-01-01