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 mechan...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 present study demonstrated that PMFs could potentially reverse PTX resistance in colon cancer by regulating the aerobic glycolysis-ROS-autophagy signaling axis,which indicated that PMFs would be potential potentiators for future chemotherapeutic agents in colon cancer.展开更多
Our recent studies demonstrated that the natural product nobiletin(NOB)served as a promising multidrug resistance(MDR)reversal agent and improved the effectiveness of cancer chemotherapy in vitro.However,low aqueous s...Our recent studies demonstrated that the natural product nobiletin(NOB)served as a promising multidrug resistance(MDR)reversal agent and improved the effectiveness of cancer chemotherapy in vitro.However,low aqueous solubility and difficulty in total synthesis limited its application as a therapeutic agent.To tackle these challenges,NOB was synthesized in a high yield by a concise route of six steps and fourteen derivatives were synthesized with remarkable solubility and efficacy.All the compounds showed improved sensitivity to paclitaxel(PTX)in P-glycoprotein(P-gp)overexpressing MDR cancer cells.Among them,compound 29 d exhibited water solubility 280-fold higher than NOB.A drug-resistance A549/T xenograft model showed that 29 d,at a dose of 50 mg/kg co-administered with PTX(15 mg/kg),inhibited tumor growth more effective than NOB and remarkably increased PTX concentration in the tumors via P-gp inhibition.Moreover,Western blot experiments revealed that 29 d inhibited expression of NRF2,phosphorylated ERK and AKT in MDR cancer cells,thus implying 29 d of multiple mechanisms to reverse MDR in lung cancer.展开更多
基金supported by National Natural Science Foundation of China(82104446)Guangdong Basic and Applied Basic Research Foundation(2023A1515011961)+3 种基金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).
文摘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 present study demonstrated that PMFs could potentially reverse PTX resistance in colon cancer by regulating the aerobic glycolysis-ROS-autophagy signaling axis,which indicated that PMFs would be potential potentiators for future chemotherapeutic agents in colon cancer.
基金supported by National Key R&D Program of China(2017YFB0202600)Macao Science and Technology Development Fund,Macao Special Administrative Region(003/2017/A1to Ying Xie,China)+1 种基金National Natural Science Foundation of China(21572279,21877134,81602955 and 81703341)Guangdong Province Higher Vocational Colleges&Schools Pearl River Scholar Funded Scheme(2016,China).
文摘Our recent studies demonstrated that the natural product nobiletin(NOB)served as a promising multidrug resistance(MDR)reversal agent and improved the effectiveness of cancer chemotherapy in vitro.However,low aqueous solubility and difficulty in total synthesis limited its application as a therapeutic agent.To tackle these challenges,NOB was synthesized in a high yield by a concise route of six steps and fourteen derivatives were synthesized with remarkable solubility and efficacy.All the compounds showed improved sensitivity to paclitaxel(PTX)in P-glycoprotein(P-gp)overexpressing MDR cancer cells.Among them,compound 29 d exhibited water solubility 280-fold higher than NOB.A drug-resistance A549/T xenograft model showed that 29 d,at a dose of 50 mg/kg co-administered with PTX(15 mg/kg),inhibited tumor growth more effective than NOB and remarkably increased PTX concentration in the tumors via P-gp inhibition.Moreover,Western blot experiments revealed that 29 d inhibited expression of NRF2,phosphorylated ERK and AKT in MDR cancer cells,thus implying 29 d of multiple mechanisms to reverse MDR in lung cancer.
