The superiority of PMFs on reversing drug resistance of colon cancer and the effect on aerobic glycolysis-ROS-autophagy signaling axis  

作　　者：YUQIN YIN YU WU HONGLIANG HUANG YINGYING DUAN ZHONGWEN YUAN LIHUI CAO JINJIN YING YONGHENG ZHOU SENLING FENG 

机构地区：[1]Department of Pharmacy,Guangdong Provincial Key Laboratory of Major Obstetric Diseases,Guangdong Provincial Clinical Research Center for Obstetrics and Gynecology,The Third Affiliated Hospital of Guangzhou Medical University,Guangzhou,510150,China [2]School of Pharmaceutical Sciences,Guangzhou Medical University,Guangzhou,511436,China [3]Department of Pharmacy,The Fourth Affiliated Hospital of Guangzhou Medical University,Guangzhou,511300,China

出　　处：《Oncology Research》2024年第12期1891-1902,共12页肿瘤学研究（英文）

基　　金：supported by National Natural Science Foundation of China(82104446);Guangdong Basic and Applied Basic Research Foundation(2023A1515011961);Guangdong Province Characteristic Innovation Project of Universities(2022KTSCX100);Guangzhou University(College)-(High Level University/Deng feng Hospital)Basic and Applied Basic Research Project(2023A03J0397);Guangdong Medical Science and Technology Research Foundation(A2023460);Plan on Enhancing Scientific Research in GMU(2024SRP117).

摘　　要：Background:Polymethoxylatedflavones(PMFs)are compounds present in citrus peels and other Rutaceae plants,which exhibit diverse biological activities,including robust antitumor and antioxidant effects.However,the mechanism of PMFs in reversing drug resistance to colon cancer remains unknown.In the present study,we aimed to investigate the potential connection between the aerobic glycolysis-ROS-autophagy signaling axis and the reversal of PTX resistance in colon cancer by PMFs.Methods:MTT Cell viability assay and colony formation assay were used to investigate the effect of PMFs combined with PTX in reversing HCT8/T cell resistance ex vivo;the mRNA and protein levels of the target were detected by SDS-PAGE(sodium dodecyl sulfate-polyacrylamide gel electrophoresis),quantitative real-timefluorescence polymerase chain reaction(qRT-PCR)and Western blot protein immunoblotting(WB);An HCT8/T cell xenograft model was established to investigate the MDR reversal activity of PMFs in vivo;The extracellular acidification rate(ECAR)and the oxygen consumption rate(OCR)were detected to assess the cellular oxygen consumption rate and glycolytic process.Results:HCT8/T cells demonstrated significant resistance to PTX,up-regulating the expression levels of ABCB1 mRNA,P-gp,LC3-I,and LC3-II protein,and increasing intracellular reactive oxygen species(ROS)content.PMFs mainly contain two active ingredients,nobiletin,and tangeretin,which were able to reverse drug resistance in HCT8/T cells in a concentration-dependent manner.PMFs exhibited high tolerance in the HCT8/T nude mouse model while increasing the sensitivity of PTX-resistant cells and suppressing tumor growth significantly.PMFs combined with PTX reduced extracellular acidification rate(ECAR)and oxygen consumption rate(OCR)in HCT8/T cells.Additionally,PMFs reduced intracellular ROS content,down-regulated the expression levels of autophagy-related proteins LC3-I,LC3-II,Beclin1,and ATG7,and significantly reduced the number of autophagosomes in HCT8/T cells.Conclusions:The pres

关 键 词：Polymethoxylated flavones(PMFs) Colon cancer Drug resistance Aerobic glycolysis-ROS-autophagy Warburg effect 

分 类 号：R735.35[医药卫生—肿瘤]