Essential amino acids(EAAs)deprivation is a potential antitumor approach because EAAs are critical for tumor growth.To efficiently inhibit tumor growth,continuous deprivation of EAAs is required,how-ever,continuous de...Essential amino acids(EAAs)deprivation is a potential antitumor approach because EAAs are critical for tumor growth.To efficiently inhibit tumor growth,continuous deprivation of EAAs is required,how-ever,continuous deprivation without precise control will introduce toxicity to normal cells.Herein,a programmable double-unlock nanocomplex(ROCK)was prepared,which could self-supply phenylalanine ammonia-lyase(PAL)to tumor cells for phenylalanine(Phe)deprivation.ROCK was double-locked in physiological conditions when administered systemically.While ROCK actively targeted to tumor cells by integrinαvβ3/5 and CD44,ROCK was firstly unlocked by cleavage of protease on tumor cell membrane,exposing CendR and R8 to enhance endocytosis.Then,hyaluronic acid was digested by hyaluronidase overexpressed in endo/lysosome of tumor cells,in which ROCK was secondly unlocked,resulting in pro-moting endo/lysosome escape and PAL plasmid(pPAL)release.Released pPAL could sustainably express PAL in host tumor cells until the self-supplied PAL precisely and successfully deprived Phe,thereby block-ing the protein synthesis and killing tumor cells specifically.Overall,our precise Phe deprivation strategy effectively inhibited tumor growth with no observable toxicity to normal cells,providing new insights to efficiently remove intratumoral nutrition for cancer therapy.展开更多
Ferroptosis, a form of iron-dependent cell death characterized by lipid peroxidation, has emerged as a promising strategy to overcome resistance to chemotherapy. This review explores the mechanisms of ferroptosis and ...Ferroptosis, a form of iron-dependent cell death characterized by lipid peroxidation, has emerged as a promising strategy to overcome resistance to chemotherapy. This review explores the mechanisms of ferroptosis and its potential to reverse drug resistance in digestive system cancers. We summarize recent advances in understanding the GPX4-regulated pathway, iron metabolism, and lipid peroxidation as key drivers of ferroptosis. It also highlights the roles of tumor heterogeneity, tumor-stroma interactions, abnormal apoptosis, metabolic alterations, and the tumor microenvironment in drug resistance. Specific mechanisms of ferroptosis resistance in esophageal squamous cell carcinoma, gastric cancer, hepatocellular carcinoma, pancreatic ductal adenocarcinoma, and colorectal cancer are discussed, along with strategies to induce ferroptosis to reverse drug resistance. Future research should focus on translating these findings into clinical applications through targeted therapies and combination treatments to improve patient outcomes.展开更多
The incidence and mortality rates of cancer are increasing every year worldwide but the survival rate of cancer patients is still unsatisfactory.Therefore,it is necessary to further elucidate the molecular mechanisms ...The incidence and mortality rates of cancer are increasing every year worldwide but the survival rate of cancer patients is still unsatisfactory.Therefore,it is necessary to further elucidate the molecular mechanisms involved in tumor development and drug resis-tance to improve cancer cure or survival rates.In recent years,autophagy has become a hot topic in the field of oncology research,which plays a double-edged role in tumorigenesis,pro-gression,and drug resistance.Meanwhile,long non-coding RNA(lncRNA)has also been shown to regulate autophagy,and the two-sided nature of autophagy determines the dual regulatory role of autophagy-related IncRNAs(ARlncRNAs).Therefore,ARlncRNAs can be effective ther-apeutic targets for various cancers.Furthermore,the high abundance and stability of ARlncR-NAs in tumor tissues make them promising biomarkers.In this review,we summarized the roles and mechanisms of ARlncRNAs in tumor cell proliferation,apoptosis,migration,invasion,drug resistance,angiogenesis,radiation resistance,and immune regulation.In addition,we described the clinical significance of these ARlncRNAs,including as biomarkers/therapeutic targets and their association with clinical drugs.展开更多
基金supported by funds of Sichuan Province for Distinguished Young Scholar(No.2021JDJQ0037)the National Natural Science Foundation of China(No.82172094).
文摘Essential amino acids(EAAs)deprivation is a potential antitumor approach because EAAs are critical for tumor growth.To efficiently inhibit tumor growth,continuous deprivation of EAAs is required,how-ever,continuous deprivation without precise control will introduce toxicity to normal cells.Herein,a programmable double-unlock nanocomplex(ROCK)was prepared,which could self-supply phenylalanine ammonia-lyase(PAL)to tumor cells for phenylalanine(Phe)deprivation.ROCK was double-locked in physiological conditions when administered systemically.While ROCK actively targeted to tumor cells by integrinαvβ3/5 and CD44,ROCK was firstly unlocked by cleavage of protease on tumor cell membrane,exposing CendR and R8 to enhance endocytosis.Then,hyaluronic acid was digested by hyaluronidase overexpressed in endo/lysosome of tumor cells,in which ROCK was secondly unlocked,resulting in pro-moting endo/lysosome escape and PAL plasmid(pPAL)release.Released pPAL could sustainably express PAL in host tumor cells until the self-supplied PAL precisely and successfully deprived Phe,thereby block-ing the protein synthesis and killing tumor cells specifically.Overall,our precise Phe deprivation strategy effectively inhibited tumor growth with no observable toxicity to normal cells,providing new insights to efficiently remove intratumoral nutrition for cancer therapy.
基金supported by the National Natural Science Foundation of China(No.82305011).
文摘Ferroptosis, a form of iron-dependent cell death characterized by lipid peroxidation, has emerged as a promising strategy to overcome resistance to chemotherapy. This review explores the mechanisms of ferroptosis and its potential to reverse drug resistance in digestive system cancers. We summarize recent advances in understanding the GPX4-regulated pathway, iron metabolism, and lipid peroxidation as key drivers of ferroptosis. It also highlights the roles of tumor heterogeneity, tumor-stroma interactions, abnormal apoptosis, metabolic alterations, and the tumor microenvironment in drug resistance. Specific mechanisms of ferroptosis resistance in esophageal squamous cell carcinoma, gastric cancer, hepatocellular carcinoma, pancreatic ductal adenocarcinoma, and colorectal cancer are discussed, along with strategies to induce ferroptosis to reverse drug resistance. Future research should focus on translating these findings into clinical applications through targeted therapies and combination treatments to improve patient outcomes.
基金supported by the Xinglin project of Chengdu University of Traditional Chinese Medicine,Sichuan,China(No.ZKYY2019,MPRC2021012).
文摘The incidence and mortality rates of cancer are increasing every year worldwide but the survival rate of cancer patients is still unsatisfactory.Therefore,it is necessary to further elucidate the molecular mechanisms involved in tumor development and drug resis-tance to improve cancer cure or survival rates.In recent years,autophagy has become a hot topic in the field of oncology research,which plays a double-edged role in tumorigenesis,pro-gression,and drug resistance.Meanwhile,long non-coding RNA(lncRNA)has also been shown to regulate autophagy,and the two-sided nature of autophagy determines the dual regulatory role of autophagy-related IncRNAs(ARlncRNAs).Therefore,ARlncRNAs can be effective ther-apeutic targets for various cancers.Furthermore,the high abundance and stability of ARlncR-NAs in tumor tissues make them promising biomarkers.In this review,we summarized the roles and mechanisms of ARlncRNAs in tumor cell proliferation,apoptosis,migration,invasion,drug resistance,angiogenesis,radiation resistance,and immune regulation.In addition,we described the clinical significance of these ARlncRNAs,including as biomarkers/therapeutic targets and their association with clinical drugs.
