Despite advances in current anti-cancer therapies,challenges such as drug resistance,toxicity,and tumor heterogeneity persist.The limitations of traditional single-target drugs and simple combination therapies are bec...Despite advances in current anti-cancer therapies,challenges such as drug resistance,toxicity,and tumor heterogeneity persist.The limitations of traditional single-target drugs and simple combination therapies are becoming increasingly apparent1.To address these issues,a novel treatment strategy,the artificially intelligent synergistic engineered drug(AISED)paradigm,merits further exploration.This paradigm is based on the systematic engineered integration of multiple active ingredients into a unified single entity through artificial intelligence(AI).This strategy is aimed at developing new anti-cancer drug designs involving multiple ingredients,multiple molecular targets,and multiple biological effects,for multiple cancer types,thereby providing a novel theoretical paradigm for overcoming existing treatment bottlenecks.展开更多
Objective:Erianin has potential anticancer activities,especially against lung cancer.The specific mechanisms underlying the anticancer effects,including the molecular targets and signaling pathways in lung cancer,rema...Objective:Erianin has potential anticancer activities,especially against lung cancer.The specific mechanisms underlying the anticancer effects,including the molecular targets and signaling pathways in lung cancer,remain poorly understood and necessitate further investigation.Methods:Lung cancer cell viability was evaluated using the CCK-8 assay.Flow cytometry was used to examine the effects of erianin on apoptosis and cell cycle progression.m RNA sequencing and metabolomics analysis were utilized to explore erianin-induced biological changes.Potential targets were identified and validated through molecular docking and Western blot analysis.The roles of mammalian target of rapamycin(m TOR)and carbamoyl-phosphate synthetase/aspartate transcarbamylase/dihydroorotase(CAD)in erianin-induced growth inhibition were studied using gene overexpression/knockdown techniques with uridine and aspartate supplementation confirming pyrimidine metabolism involvement.Additionally,lung cancer-bearing nude mouse models were established to evaluate the anti-lung cancer effects of erianin in vivo.Results:Erianin significantly inhibits the proliferation of lung cancer cells,induces apoptosis,and causes G2/M phase cell cycle arrest.Integrative analysis of m RNA sequencing and metabolomics data demonstrated that erianin disrupts pyrimidine metabolism in lung cancer cells.Notably,uridine supplementation mitigated the inhibitory effects of erianin,establishing a connection between pyrimidine metabolism and anticancer activity.Network pharmacology analyses identified m TOR as a key target of erianin.Erianin inhibited m TOR phosphorylation,thereby blocking downstream effectors(S6K and CAD),which are essential regulators of pyrimidine metabolism.Conclusions:Erianin is a promising therapeutic candidate for lung cancer.Erianin likely inhibits lung cancer cell growth by disrupting pyrimidine metabolism by suppressing m TOR activation.展开更多
Natural products(NPs)have long been recognized for their therapeutic potential,especially in cancer treatment,due to an ability to interact with multiple cellular pathways.The identification of molecular targets for N...Natural products(NPs)have long been recognized for their therapeutic potential,especially in cancer treatment,due to an ability to interact with multiple cellular pathways.The identification of molecular targets for NPs is a critical step in understanding anticancer mechanisms,with chemical proteomics emerging as a powerful approach.Both label-based and-free proteomic techniques have been utilized to identify these targets,each with their own advantages and limitations.While label-based methods provide high specificity through chemical tagging,the requirement for labeling can be a limitation,potentially altering NP natural properties.Conversely,label-free techniques allow for the detection of NP-protein interactions without structural modification but may struggle with transient interactions or low-abundance targets.Recent advances in artificial intelligence(AI)have further enhanced the field by improving target prediction and streamlining data analysis.AI-driven models,especially machine learning algorithms,have proven effective in processing complex proteomic data and predicting potential NP-protein interactions.The integration of AI with chemical proteomics accelerates target identification and deepens our understanding of the molecular mechanisms underlying the anticancer effects of NPs.This review explores the application of chemical proteomics and AI in the identification of cancer-related targets for NPs,highlighting current challenges and future directions for clinical translation.展开更多
Autophagy is a conserved intracellular degradation system that plays a dual role in cell death;thus,therapies targeting autophagy in cancer are somewhat controversial.Ferroptosis is a new form of regulated cell death ...Autophagy is a conserved intracellular degradation system that plays a dual role in cell death;thus,therapies targeting autophagy in cancer are somewhat controversial.Ferroptosis is a new form of regulated cell death featured with the iron-dependent accumulation of lethal lipid ROS.This pathway is morphologically,biochemically and genetically distinct from other forms of cell death.Accumulating studies have revealed crosstalk between autophagy and ferroptosis at the molecular level.In this review,we summarize the mechanisms of ferroptosis and autophagy,and more importantly,their roles in the drug resistance of cancer.Numerous connections between ferroptosis and autophagy have been revealed,and a strong causal relationship exists wherein one process controls the other and can be utilized as potential therapeutic targets for cancer.The elucidation of when and how to modulate their crosstalk using therapeutic strategies depends on an understanding of the fine-tuned switch between ferroptosis and autophagy,and approaches designed to manipulate the intensity of autophagy might be the key.展开更多
Objective:This study aimed to develop a new polyethylene glycol(PEG)ylatedβ-elemene liposome(PEG-Lipo-β-E)and evaluate its characterization,pharmacokinetics,antitumor effects and safety in vitro and in vivo.Methods:...Objective:This study aimed to develop a new polyethylene glycol(PEG)ylatedβ-elemene liposome(PEG-Lipo-β-E)and evaluate its characterization,pharmacokinetics,antitumor effects and safety in vitro and in vivo.Methods:The liposomes were prepared by ethanol injection and high-pressure micro-jet homogenization.Characterization of the liposomes was conducted,and drug content,entrapment efficiency(EE),in vitro release and stability were studied by ultra-fast liquid chromatography(UFLC)and a liquid surface method.Blood was drawn from rats to establish the pharmacokinetic parameters.The anticancer effect was evaluated in a KU-19-19 bladder cancer xenograft model.Histological analyses were performed to evaluate safety.Results:The PEG-Lipo-β-E showed good stability and was characterized as 83.31±0.181 nm in size,0.279±0.004 in polydispersity index(PDI),-21.4±1.06 mV in zeta potential,6.65±0.02 in pH,5.024±0.107 mg/mL inβ-elemene(β-E)content,and 95.53±1.712%in average EE.The Fourier transform infrared spectroscopy(FTIR)and differential scanning calorimetry(DSC)indicated the formation of PEG-Lipo-β-E.Compared to elemene injection,PEG-Lipo-β-E demonstrated a 1.75-fold decrease in clearance,a 1.62-fold increase in half-life,and a 1.76-fold increase in area under the concentration-time curves(AUCs)from 0 hour to 1.5 hours(P<0.05).PEG-Lipo-β-E also showed an enhanced anticancer effect in vivo.Histological analyses showed that there was no evidence of toxicity to the heart,kidney,liver,lung or spleen.Conclusions:The present study demonstrates PEG-Lipo-β-E as a new formulation with ease of preparation,high EE,good stability,improved bioavailability and antitumor effects.展开更多
Objective:In this study,we aimed to develop an amino-terminal fragment(ATF)peptide-targeted liposome carryingβ-elemene(ATF24-PEG-Lipo-β-E)for targeted delivery into urokinase plasminogen activator receptor-overexpre...Objective:In this study,we aimed to develop an amino-terminal fragment(ATF)peptide-targeted liposome carryingβ-elemene(ATF24-PEG-Lipo-β-E)for targeted delivery into urokinase plasminogen activator receptor-overexpressing bladder cancer cells combined with cisplatin(DDP)for bladder cancer treatment.Methods:The liposomes were prepared by ethanol injection and high-pressure microjet homogenization.The liposomes were characterized,and the drug content,entrapment efficiency,andin vitro release were studied.The targeting efficiency was investigated using confocal microscopy,ultra-fast liquid chromatography,and an orthotopic bladder cancer model.The effects of ATF24-PEG-Lipo-β-E combined with DDP on cell viability and proliferation were evaluated by a Cell Counting Kit-8(CCK-8)assay,a colony formation assay,and cell apoptosis and cell cycle analyses.The anticancer effects were evaluated in a KU-19-19 bladder cancer xenograft model.Results:ATF24-PEG-Lipo-β-E had small and uniform sizes(~79 nm),high drug loading capacity(~5.24 mg/mL),high entrapment efficiency(98.37±0.95%),and exhibited sustained drug release behavior.ATF24-PEG-Lipo-β-E had better targeting efficiency and higher cytotoxicity than polyethylene glycol(PEG)ylatedβ-elemene liposomes(PEG-Lipo-β-E).DDP,combined with ATF24-PEG-Lipo-β-E,exerted a synergistic effect on cellular apoptosis and cell arrest at the G2/M phase,and these effects were dependent on the caspase-dependent pathway and Cdc25C/Cdc2/cyclin B1 pathways.Furthermore,thein vivo antitumor activity showed that the targeted liposomes effectively inhibited the growth of tumors,using the combined strategy.Conclusions:The present study provided an effective strategy for the targeted delivery ofβ-elemene(β-E)to bladder cancer,and a combined strategy for bladder cancer treatment.展开更多
Ferroptosis is a non-apoptotic regulated cell death caused by iron accumulation and subsequent lipid peroxidation.Currently,the therapeutic role of ferroptosis on cancer is gaining increasing interest.Baicalin an acti...Ferroptosis is a non-apoptotic regulated cell death caused by iron accumulation and subsequent lipid peroxidation.Currently,the therapeutic role of ferroptosis on cancer is gaining increasing interest.Baicalin an active component in Scutellaria baicalensis Georgi with anticancer potential various cancer types;however,the effects of baicalein on bladder cancer and the underlying molecular mechanisms remain largely unknown.In the study,we investigated the effect of baicalin on bladder cancer cells5637 and KU-19-19.As a result,we show baicalin exerted its anticancer activity by inducing apoptosis and cell death in bladder cancer cells.Subsequently,we for the first time demonstrate baicalin-induced ferroptotic cell death in vitro and in vivo,accompanied by reactive oxygen species(ROS) accumulation and intracellular chelate iron enrichment.The ferroptosis inhibitor deferoxamine but not necrostatin-1,chloroquine(CQ),N-acetyl-L-cysteine,L-glutathione reduced,or carbobenzoxy-valyl-alanyl-aspartyl-[O-methyl]-fluoromethylketone(Z-VAD-FMK) rescued baicalin-induced cell death,indicating ferroptosis contributed to baicalin-induced cell death.Mechanistically,we show that ferritin heavy chain1(FTH1) was a key determinant for baicalin-induced ferroptosis.Overexpression of FTH1 abrogated the anticancer effects of baicalin in both 5637 and KU19-19 cells.Taken together,our data for the first time suggest that the natural product baicalin exerts its anticancer activity by inducing FTH1-dependent ferroptosis,which will hopefully provide a prospective compound for bladder cancer treatment.展开更多
Curcumenol,an effective ingredient of Wenyujin,has been reported that exerted its antitumor potential in a few cancer types.However,the effect and molecular mechanism of curcumenol in lung cancer are largely unknown.H...Curcumenol,an effective ingredient of Wenyujin,has been reported that exerted its antitumor potential in a few cancer types.However,the effect and molecular mechanism of curcumenol in lung cancer are largely unknown.Here,we found that curcumenol induced cell death and suppressed cell proliferation in lung cancer cells.Next,we demonstrated that ferroptosis was the predominant method that contributed to curcumenol-induced cell death of lung cancer in vitro and vivo for the first time.Subsequently,using RNA sequencing,we found that the long non-coding RNA H19(lncRNA H19)was significantly downregulated in lung cancer cells treated with curcumenol,when compared to untreated controls.Overexpression of lncRNA H19 eliminated the anticancer effect of curcumenol,while lncRNA H19 knockdown promoted ferroptosis induced by curcumenol treatment.Mechanistically,we showed that lncRNA H19 functioned as a competing endogenous RNA to bind to miR-19b-3p,thereby enhanced the transcription activity of its endogenous target,ferritin heavy chain 1(FTH1),a marker of ferroptosis.In conclusion,our data show that the natural product curcumenol exerted its antitumor effects on lung cancer by triggering ferroptosis,and the lncRNA H19/miR-19b-3p/FTH1 axis plays an essential role in curcumenol-induced ferroptotic cell death.Therefore,our findings will hopefully provide a valuable drug for treating lung cancer patients.展开更多
Ferroptosis,a novel form of programmed cell death,is characterized by iron-dependent lipid peroxidation and has been shown to be involved in multiple diseases,including cancer.Stimulating ferroptosis in cancer cells m...Ferroptosis,a novel form of programmed cell death,is characterized by iron-dependent lipid peroxidation and has been shown to be involved in multiple diseases,including cancer.Stimulating ferroptosis in cancer cells may be a potential strategy for cancer therapy.Therefore,ferroptosis-inducing drugs are attracting more attention for cancer treatment.Here,we showed that erianin,a natural product isolated from Dendrobium chrysotoxum Lindl,exerted its anticancer activity by inducing cell death and inhibiting cell migration in lung cancer cells.Subsequently,we demonstrated for the first time that erianin induced ferroptotic cell death in lung cancer cells,which was accompanied by ROS accumulation,lipid peroxidation,and GSH depletion.The ferroptosis inhibitors Fer-1 and Lip-1 but not Z-VAD-FMK,CQ,or necrostatin-1 rescued erianin-induced cell death,indicating that ferroptosis contributed to erianin-induced cell death.Furthermore,we demonstrated that Ca^(2+)/CaM signaling was a critical mediator of erianin-induced ferroptosis and that blockade of this signaling significantly rescued cell death induced by erianin treatment by suppressing ferroptosis.Taken together,our data suggest that the natural product erianin exerts its anticancer effects by inducing Ca^(2+)/CaMdependent ferroptosis and inhibiting cell migration,and erianin will hopefully serve as a prospective compound for lung cancer treatment.展开更多
5-Fluorouracil(5-FU)is known as a first-line chemotherapeutic agent against colorectal cancer(CRC),but drug resistance occurs frequently and significantly limits its clinical success.Our previous study showed that the...5-Fluorouracil(5-FU)is known as a first-line chemotherapeutic agent against colorectal cancer(CRC),but drug resistance occurs frequently and significantly limits its clinical success.Our previous study showed that the protocadherin 17(PCDH17)gene was frequently methylated and functioned as a tumor suppressor in CRC.However,the relationship between PCDH17 and 5-FU resistance in CRC remains unclear.Here,we revealed that PCDH17 was more highly expressed in 5-FU-sensitive CRC tissues than in 5-FU-resistant CRC tissues,and high expression of PCDH17 was correlated with high BECN1 expression.Moreover,this expression profile contributed to superior prognosis and increased survival in CRC patients.Restoring PCDH17 expression augmented the 5-FU sensitivity of CRC in vitro and in vivo by promoting apoptosis and autophagic cell death.Furthermore,autophagy played a dominant role in PCDH17-induced cell death,as an autophagy inhibitor blocked cell death to a greater extent than the pancaspase inhibitor Z-VAD-FMK.PCDH17 inhibition by siRNA decreased the autophagy response and 5-FU sensitivity.Mechanistically,we showed that c-Jun NH2-terminal kinase(JNK)activation was a key determinant in PCDH17-induced autophagy.The compound SP600125,an inhibitor of JNK,suppressed autophagy and 5-FU-induced cell death in PCDH17-reexpressing CRC cells.Taken together,our findings suggest for the first time that PCDH17 increases the sensitivity of CRC to 5-FU treatment by inducing apoptosis and JNK-dependent autophagic cell death.PCDH17 may be a potential prognostic marker for predicting 5-FU sensitivity in CRC patients.展开更多
Accumulating evidence suggests that chronic inflammation may play a critical role in various malignancies,including bladder cancer.This hypothesis stems in part from inflammatory cells observed in the urethral microen...Accumulating evidence suggests that chronic inflammation may play a critical role in various malignancies,including bladder cancer.This hypothesis stems in part from inflammatory cells observed in the urethral microenvironment.Chronic inflammation may drive neoplastic transformation and the progression of bladder cancer by activating a series of in-flammatory molecules and signals.Recently,it has been shown that the microbiome also plays an important role in the development and progression of bladder cancer,which can be mediated through the stimulation of chronic inflammation.In effect,the urinary microbiome can play a role in establishing the inflammatory urethral microenvironment that may facilitate the development and progression of bladder cancer.In other words,chronic inflammation caused by the urinary microbiome may promote the initiation and progression of bladder cancer.Here,we provide a detailed and comprehensive account of the link between chronic inflammation,the microbiome and bladder cancer.Finally,we highlight that targeting the urinary microbiome might enable the development of strategies for bladder cancer prevention and personalized treatment.展开更多
Non-genetic mechanisms have recently emerged as important drivers of anticancer drug resistance.Among these,the drug tolerant persister(DTP)cell phenotype is attracting more and more attention and giving a predominant...Non-genetic mechanisms have recently emerged as important drivers of anticancer drug resistance.Among these,the drug tolerant persister(DTP)cell phenotype is attracting more and more attention and giving a predominant non-genetic role in cancer therapy resistance.The DTP phenotype is characterized by a quiescent or slow-cell-cycle reversible state of the cancer cell subpopulation and inert specialization to stimuli,which tolerates anticancer drug exposure to some extent through the interaction of multiple underlying mechanisms and recovering growth and proliferation after drug withdrawal,ultimately leading to treatment resistance and cancer recurrence.Therefore,targeting DTP cells is anticipated to provide new treatment opportunities for cancer patients,although our current knowledge of these DTP cells in treatment resistance remains limited.In this review,we provide a comprehensive overview of the formation characteristics and underlying drug tolerant mechanisms of DTP cells,investigate the potential drugs for DTP(including preclinical drugs,novel use for old drugs,and natural products)based on different medicine models,and discuss the necessity and feasibility of anti-DTP therapy,related application forms,and future issues that will need to be addressed to advance this emerging field towards clinical applications.Nonetheless,understanding the novel functions of DTP cells may enable us to develop new more effective anticancer therapy and improve clinical outcomes for cancer patients.展开更多
Background:Bladder cancer is a highly prevalent and lethal malignant tumor characterized by frequent mutations/deletions of lysine-specific demethylase 6A(KDM6A),which is suggested to be a key event in cancer progress...Background:Bladder cancer is a highly prevalent and lethal malignant tumor characterized by frequent mutations/deletions of lysine-specific demethylase 6A(KDM6A),which is suggested to be a key event in cancer progression and metastasis.Beta-elemene has been shown to inhibit metastasis and growth of various tumors,but its effect on KDM6A-null bladder cancer cells remains unknown.Objective:This study aimed to investigate the potential and molecular mechanism ofβ-elemene in inhibiting the growth of KDM6A-null bladder cancer.Methods:This study examined the migration ability and viability of RT-4(KDM6A wild-type)and KU19-19(KDM6A-null)cell lines using wound healing assay and CCK-8,respectively.The inhibitory effect ofβ-elemene on KU19-19 cell migration was evaluated using transwell and immunofluorescence assays,and the expression of transfer-related proteins and genes was analyzed through western blot and qRT-PCR,respectively.Molecular docking was performed to predict the targeting ofβ-elemene,and the effects were confirmed in KDM6Aknockdown RT-4 cells.Finally,the therapeutic effect ofβ-elemene on bladder cancer was tested in animal models.Results:The study observed that loss of KDM6A increased bladder cancer cell migration,with KU19-19 exhibiting significantly stronger migration than RT-4.Further investigation revealed thatβ-elemene effectively inhibited KU19-19 cell migration,likely through targeting EZH2 as determined by molecular docking.Overexpression of KDM6A inhibited KU19-19 metastasis,while knockdown of KDM6A in RT-4 cells enhanced cell migration,which was reversed byβ-elemene treatment.Notably,in vivo testing revealed a significant suppression of KU19-19 cell growth withβ-elemene administered at a dosage of 100 mg/kg.Conclusion:β-elemene has the potential to suppress the growth of KDM6A-null bladder cancer by inhibiting epithelial-mesenchymal transition(EMT),which could make it a promising therapeutic option for patients with KDM6A-null bladder cancer.展开更多
文摘Despite advances in current anti-cancer therapies,challenges such as drug resistance,toxicity,and tumor heterogeneity persist.The limitations of traditional single-target drugs and simple combination therapies are becoming increasingly apparent1.To address these issues,a novel treatment strategy,the artificially intelligent synergistic engineered drug(AISED)paradigm,merits further exploration.This paradigm is based on the systematic engineered integration of multiple active ingredients into a unified single entity through artificial intelligence(AI).This strategy is aimed at developing new anti-cancer drug designs involving multiple ingredients,multiple molecular targets,and multiple biological effects,for multiple cancer types,thereby providing a novel theoretical paradigm for overcoming existing treatment bottlenecks.
基金supported by the National Natural Science Foundation of China(82104207)Natural Science Foundation of Zhejiang Province(LQ22H280001)。
文摘Objective:Erianin has potential anticancer activities,especially against lung cancer.The specific mechanisms underlying the anticancer effects,including the molecular targets and signaling pathways in lung cancer,remain poorly understood and necessitate further investigation.Methods:Lung cancer cell viability was evaluated using the CCK-8 assay.Flow cytometry was used to examine the effects of erianin on apoptosis and cell cycle progression.m RNA sequencing and metabolomics analysis were utilized to explore erianin-induced biological changes.Potential targets were identified and validated through molecular docking and Western blot analysis.The roles of mammalian target of rapamycin(m TOR)and carbamoyl-phosphate synthetase/aspartate transcarbamylase/dihydroorotase(CAD)in erianin-induced growth inhibition were studied using gene overexpression/knockdown techniques with uridine and aspartate supplementation confirming pyrimidine metabolism involvement.Additionally,lung cancer-bearing nude mouse models were established to evaluate the anti-lung cancer effects of erianin in vivo.Results:Erianin significantly inhibits the proliferation of lung cancer cells,induces apoptosis,and causes G2/M phase cell cycle arrest.Integrative analysis of m RNA sequencing and metabolomics data demonstrated that erianin disrupts pyrimidine metabolism in lung cancer cells.Notably,uridine supplementation mitigated the inhibitory effects of erianin,establishing a connection between pyrimidine metabolism and anticancer activity.Network pharmacology analyses identified m TOR as a key target of erianin.Erianin inhibited m TOR phosphorylation,thereby blocking downstream effectors(S6K and CAD),which are essential regulators of pyrimidine metabolism.Conclusions:Erianin is a promising therapeutic candidate for lung cancer.Erianin likely inhibits lung cancer cell growth by disrupting pyrimidine metabolism by suppressing m TOR activation.
基金supported in part by the Science and Technology Development Fund,Macao SAR(0098/2021/A2 and 0048/2023/AFJ)the Chinese Medicine Guangdong Laboratory(HQCML-C-2024006).
文摘Natural products(NPs)have long been recognized for their therapeutic potential,especially in cancer treatment,due to an ability to interact with multiple cellular pathways.The identification of molecular targets for NPs is a critical step in understanding anticancer mechanisms,with chemical proteomics emerging as a powerful approach.Both label-based and-free proteomic techniques have been utilized to identify these targets,each with their own advantages and limitations.While label-based methods provide high specificity through chemical tagging,the requirement for labeling can be a limitation,potentially altering NP natural properties.Conversely,label-free techniques allow for the detection of NP-protein interactions without structural modification but may struggle with transient interactions or low-abundance targets.Recent advances in artificial intelligence(AI)have further enhanced the field by improving target prediction and streamlining data analysis.AI-driven models,especially machine learning algorithms,have proven effective in processing complex proteomic data and predicting potential NP-protein interactions.The integration of AI with chemical proteomics accelerates target identification and deepens our understanding of the molecular mechanisms underlying the anticancer effects of NPs.This review explores the application of chemical proteomics and AI in the identification of cancer-related targets for NPs,highlighting current challenges and future directions for clinical translation.
基金supported by the National Natural Science Foundation of China (Grant No. 81602471, 81672729, 81672729, 81874380 and 81672932)Zhejiang Provincial Natural Science Foundation of China under Grants (Grant No. LY19H160055, LY19H160059)+5 种基金by Zheng Shu Medical Elite Scholarship Fundby grant from sub-project of China National Program on Key Basic Research Project (973 Program) (Grant No. 2014CB744505)Zhejiang Provincial Natural Science Foundation of China for Distinguished Young Scholars (Grant No. LR18H160001)Zhejiang Province Medical Science and Technology Project (Grant No. 2017RC007)Talent Project of Zhejiang Association for Science and Technology (Grant No. 2017YCGC002)Zhejiang Province Science and Technology Project of TCM (Grant No. 2019ZZ016)
文摘Autophagy is a conserved intracellular degradation system that plays a dual role in cell death;thus,therapies targeting autophagy in cancer are somewhat controversial.Ferroptosis is a new form of regulated cell death featured with the iron-dependent accumulation of lethal lipid ROS.This pathway is morphologically,biochemically and genetically distinct from other forms of cell death.Accumulating studies have revealed crosstalk between autophagy and ferroptosis at the molecular level.In this review,we summarize the mechanisms of ferroptosis and autophagy,and more importantly,their roles in the drug resistance of cancer.Numerous connections between ferroptosis and autophagy have been revealed,and a strong causal relationship exists wherein one process controls the other and can be utilized as potential therapeutic targets for cancer.The elucidation of when and how to modulate their crosstalk using therapeutic strategies depends on an understanding of the fine-tuned switch between ferroptosis and autophagy,and approaches designed to manipulate the intensity of autophagy might be the key.
基金supported by grants from National Natural Science Foundation of China(Grant No.81672932,81874380 and 81730108)Zhejiang Provincial Natural Science Foundation of China for Distinguished Young Scholars(Grant No.LR18H160001)+7 种基金Zhejiang Provincial Natural Science Foundation of China(Grant No.LY15H160028 and LY13H130002)the Science and Technology Development Fund,Macao SAR(130/2017/A3,0099/2018/A3)Zhejiang Province Medical Science and Technology Project(Grant No.2017RC007)Key Project of Zhejiang Province Ministry of Science and Technology(Grant No.2015C03055)Talent Project of Zhejiang Association for Science and Technology(Grant No.2017YCGC002)Zhejiang Province Science and Technology Project of TCM(Grant No.2019ZZ016)Key Project of Hangzhou Ministry of Science and Technology(Grant No.20162013A07,20142013A63)Zhejiang Provincial Project for the Key Discipline of Traditional Chinese Medicine(Grant No.2017-XK-A09)。
文摘Objective:This study aimed to develop a new polyethylene glycol(PEG)ylatedβ-elemene liposome(PEG-Lipo-β-E)and evaluate its characterization,pharmacokinetics,antitumor effects and safety in vitro and in vivo.Methods:The liposomes were prepared by ethanol injection and high-pressure micro-jet homogenization.Characterization of the liposomes was conducted,and drug content,entrapment efficiency(EE),in vitro release and stability were studied by ultra-fast liquid chromatography(UFLC)and a liquid surface method.Blood was drawn from rats to establish the pharmacokinetic parameters.The anticancer effect was evaluated in a KU-19-19 bladder cancer xenograft model.Histological analyses were performed to evaluate safety.Results:The PEG-Lipo-β-E showed good stability and was characterized as 83.31±0.181 nm in size,0.279±0.004 in polydispersity index(PDI),-21.4±1.06 mV in zeta potential,6.65±0.02 in pH,5.024±0.107 mg/mL inβ-elemene(β-E)content,and 95.53±1.712%in average EE.The Fourier transform infrared spectroscopy(FTIR)and differential scanning calorimetry(DSC)indicated the formation of PEG-Lipo-β-E.Compared to elemene injection,PEG-Lipo-β-E demonstrated a 1.75-fold decrease in clearance,a 1.62-fold increase in half-life,and a 1.76-fold increase in area under the concentration-time curves(AUCs)from 0 hour to 1.5 hours(P<0.05).PEG-Lipo-β-E also showed an enhanced anticancer effect in vivo.Histological analyses showed that there was no evidence of toxicity to the heart,kidney,liver,lung or spleen.Conclusions:The present study demonstrates PEG-Lipo-β-E as a new formulation with ease of preparation,high EE,good stability,improved bioavailability and antitumor effects.
基金This research was supported by grants from the National Natural Science Foundation of China(Grant Nos.81672932,81730108,81874380,and 81973635)Zhejiang Provincial Natural Science Foundation of China for Distinguished Young Scholars(Grant No.LR18H160001)the Zhejiang Province Science and Technology Project of TCM(Grant No.2019ZZ016).
文摘Objective:In this study,we aimed to develop an amino-terminal fragment(ATF)peptide-targeted liposome carryingβ-elemene(ATF24-PEG-Lipo-β-E)for targeted delivery into urokinase plasminogen activator receptor-overexpressing bladder cancer cells combined with cisplatin(DDP)for bladder cancer treatment.Methods:The liposomes were prepared by ethanol injection and high-pressure microjet homogenization.The liposomes were characterized,and the drug content,entrapment efficiency,andin vitro release were studied.The targeting efficiency was investigated using confocal microscopy,ultra-fast liquid chromatography,and an orthotopic bladder cancer model.The effects of ATF24-PEG-Lipo-β-E combined with DDP on cell viability and proliferation were evaluated by a Cell Counting Kit-8(CCK-8)assay,a colony formation assay,and cell apoptosis and cell cycle analyses.The anticancer effects were evaluated in a KU-19-19 bladder cancer xenograft model.Results:ATF24-PEG-Lipo-β-E had small and uniform sizes(~79 nm),high drug loading capacity(~5.24 mg/mL),high entrapment efficiency(98.37±0.95%),and exhibited sustained drug release behavior.ATF24-PEG-Lipo-β-E had better targeting efficiency and higher cytotoxicity than polyethylene glycol(PEG)ylatedβ-elemene liposomes(PEG-Lipo-β-E).DDP,combined with ATF24-PEG-Lipo-β-E,exerted a synergistic effect on cellular apoptosis and cell arrest at the G2/M phase,and these effects were dependent on the caspase-dependent pathway and Cdc25C/Cdc2/cyclin B1 pathways.Furthermore,thein vivo antitumor activity showed that the targeted liposomes effectively inhibited the growth of tumors,using the combined strategy.Conclusions:The present study provided an effective strategy for the targeted delivery ofβ-elemene(β-E)to bladder cancer,and a combined strategy for bladder cancer treatment.
基金supported by the grants National Natural Science Foundation of China (Nos. 81874380 and 82022075, to Xinbing Sui81730108 and 81973635, to Tian Xie)+4 种基金Zhejiang Provincial Natural Science Foundation of China for Distinguished Young Scholars (No. LR18H160001, to Xinbing Sui)Zhejiang Provincial Natural Science Foundation of China (Nos. LQ20H160013, Ting DuanLQ21H160038, to Jiao Feng)Zhejiang Province Science and Technology Project of TCM (Nos. 2019ZZ016, to Xinbing Sui2020ZQ046, to Ruonan Zhang, China)。
文摘Ferroptosis is a non-apoptotic regulated cell death caused by iron accumulation and subsequent lipid peroxidation.Currently,the therapeutic role of ferroptosis on cancer is gaining increasing interest.Baicalin an active component in Scutellaria baicalensis Georgi with anticancer potential various cancer types;however,the effects of baicalein on bladder cancer and the underlying molecular mechanisms remain largely unknown.In the study,we investigated the effect of baicalin on bladder cancer cells5637 and KU-19-19.As a result,we show baicalin exerted its anticancer activity by inducing apoptosis and cell death in bladder cancer cells.Subsequently,we for the first time demonstrate baicalin-induced ferroptotic cell death in vitro and in vivo,accompanied by reactive oxygen species(ROS) accumulation and intracellular chelate iron enrichment.The ferroptosis inhibitor deferoxamine but not necrostatin-1,chloroquine(CQ),N-acetyl-L-cysteine,L-glutathione reduced,or carbobenzoxy-valyl-alanyl-aspartyl-[O-methyl]-fluoromethylketone(Z-VAD-FMK) rescued baicalin-induced cell death,indicating ferroptosis contributed to baicalin-induced cell death.Mechanistically,we show that ferritin heavy chain1(FTH1) was a key determinant for baicalin-induced ferroptosis.Overexpression of FTH1 abrogated the anticancer effects of baicalin in both 5637 and KU19-19 cells.Taken together,our data for the first time suggest that the natural product baicalin exerts its anticancer activity by inducing FTH1-dependent ferroptosis,which will hopefully provide a prospective compound for bladder cancer treatment.
基金This work was financially funded by the grants National Natural Science Foundation of China(No.81874380 and 82022075,to Xinbing Sui,81730108 and 81973635,to Tian Xie,82104207,to Xueni Sun)Zhejiang Provincial Natural Science Foundation of China for Distinguished Young Scholars(No.LR18H160001,to Xinbing Sui)+5 种基金the Science and Technology Development Fund,Macao SAR(No.130/2017/A3,0099/2018/A3 and 0098/2021/A2,to Qibiao Wu)Science and Technology Planning Project of Guangdong Province(2020B1212030008,to Qibiao Wu)Zhejiang Provincial Natural Science Foundation of China(No.LQ20H160013,Ting DuanLQ21H160038,to Jiao Feng)Zhejiang Province Science and Technology Project of TCM(No.2019ZZ016,to Xinbing Sui2021ZQ058,to Ruonan Zhang,China).
文摘Curcumenol,an effective ingredient of Wenyujin,has been reported that exerted its antitumor potential in a few cancer types.However,the effect and molecular mechanism of curcumenol in lung cancer are largely unknown.Here,we found that curcumenol induced cell death and suppressed cell proliferation in lung cancer cells.Next,we demonstrated that ferroptosis was the predominant method that contributed to curcumenol-induced cell death of lung cancer in vitro and vivo for the first time.Subsequently,using RNA sequencing,we found that the long non-coding RNA H19(lncRNA H19)was significantly downregulated in lung cancer cells treated with curcumenol,when compared to untreated controls.Overexpression of lncRNA H19 eliminated the anticancer effect of curcumenol,while lncRNA H19 knockdown promoted ferroptosis induced by curcumenol treatment.Mechanistically,we showed that lncRNA H19 functioned as a competing endogenous RNA to bind to miR-19b-3p,thereby enhanced the transcription activity of its endogenous target,ferritin heavy chain 1(FTH1),a marker of ferroptosis.In conclusion,our data show that the natural product curcumenol exerted its antitumor effects on lung cancer by triggering ferroptosis,and the lncRNA H19/miR-19b-3p/FTH1 axis plays an essential role in curcumenol-induced ferroptotic cell death.Therefore,our findings will hopefully provide a valuable drug for treating lung cancer patients.
基金supported by grants from the National Natural Science Foundation of China(grant Nos.81672932,81730108,81874380,and 81973635)the Zhejiang Provincial Natural Science Foundation of China for Distinguished Young Scholars(grant No.LR18H160001)+1 种基金the Zhejiang Province Science and Technology Project of TCM(grant No.2019ZZ016)the Open Project Program of the Jiangsu Key Laboratory of Pharmacology and Safety Evaluation of Chinese Materia Medica(No.JKLPSE201807).
文摘Ferroptosis,a novel form of programmed cell death,is characterized by iron-dependent lipid peroxidation and has been shown to be involved in multiple diseases,including cancer.Stimulating ferroptosis in cancer cells may be a potential strategy for cancer therapy.Therefore,ferroptosis-inducing drugs are attracting more attention for cancer treatment.Here,we showed that erianin,a natural product isolated from Dendrobium chrysotoxum Lindl,exerted its anticancer activity by inducing cell death and inhibiting cell migration in lung cancer cells.Subsequently,we demonstrated for the first time that erianin induced ferroptotic cell death in lung cancer cells,which was accompanied by ROS accumulation,lipid peroxidation,and GSH depletion.The ferroptosis inhibitors Fer-1 and Lip-1 but not Z-VAD-FMK,CQ,or necrostatin-1 rescued erianin-induced cell death,indicating that ferroptosis contributed to erianin-induced cell death.Furthermore,we demonstrated that Ca^(2+)/CaM signaling was a critical mediator of erianin-induced ferroptosis and that blockade of this signaling significantly rescued cell death induced by erianin treatment by suppressing ferroptosis.Taken together,our data suggest that the natural product erianin exerts its anticancer effects by inducing Ca^(2+)/CaMdependent ferroptosis and inhibiting cell migration,and erianin will hopefully serve as a prospective compound for lung cancer treatment.
基金This research was supported by grants from the National Natural Science Foundation of China(Grant Nos.81672932,81730108,81874380,81802371,and 81973635)Zhejiang Provincial Natural Science Foundation of China for Distinguished Young Scholars(Grant No.LR18H160001)+6 种基金Zhejiang Province Science and Technology Project of TCM(Grant No.2019ZZ016)Zhejiang Province Medical Science and Technology Project(Grant No.2017RC007)Talent Project of Zhejiang Association for Science and Technology(Grant No.2017YCGC002)Key Project of Hangzhou Ministry of Science and Technology(Grant No.20162013A07)Zhejiang Provincial Project for the Key Discipline of Traditional Chinese Medicine(Grant No.2017-XK-A09)Open Project Program of Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica(No.JKLPSE201807)Project of the Priority Academic Program Development of Jiangsu Higher Education Institutions(PAPD).
文摘5-Fluorouracil(5-FU)is known as a first-line chemotherapeutic agent against colorectal cancer(CRC),but drug resistance occurs frequently and significantly limits its clinical success.Our previous study showed that the protocadherin 17(PCDH17)gene was frequently methylated and functioned as a tumor suppressor in CRC.However,the relationship between PCDH17 and 5-FU resistance in CRC remains unclear.Here,we revealed that PCDH17 was more highly expressed in 5-FU-sensitive CRC tissues than in 5-FU-resistant CRC tissues,and high expression of PCDH17 was correlated with high BECN1 expression.Moreover,this expression profile contributed to superior prognosis and increased survival in CRC patients.Restoring PCDH17 expression augmented the 5-FU sensitivity of CRC in vitro and in vivo by promoting apoptosis and autophagic cell death.Furthermore,autophagy played a dominant role in PCDH17-induced cell death,as an autophagy inhibitor blocked cell death to a greater extent than the pancaspase inhibitor Z-VAD-FMK.PCDH17 inhibition by siRNA decreased the autophagy response and 5-FU sensitivity.Mechanistically,we showed that c-Jun NH2-terminal kinase(JNK)activation was a key determinant in PCDH17-induced autophagy.The compound SP600125,an inhibitor of JNK,suppressed autophagy and 5-FU-induced cell death in PCDH17-reexpressing CRC cells.Taken together,our findings suggest for the first time that PCDH17 increases the sensitivity of CRC to 5-FU treatment by inducing apoptosis and JNK-dependent autophagic cell death.PCDH17 may be a potential prognostic marker for predicting 5-FU sensitivity in CRC patients.
基金This research was supported by grants from National Natural Science Foundation of China[grant numbers 81630080,91129714,81874380,81730108,81973635 and 82022075]Zhejiang Provincial Natural Science Foundation of China for Distinguished Young Scholars[grant number LR18H160001]+1 种基金the National Key R&D Program of China[grant numbers 2018YFC1704100 and 2018YFC1704106]Zhejiang province science and technology project of TCM[grant number 2019ZZ016].
文摘Accumulating evidence suggests that chronic inflammation may play a critical role in various malignancies,including bladder cancer.This hypothesis stems in part from inflammatory cells observed in the urethral microenvironment.Chronic inflammation may drive neoplastic transformation and the progression of bladder cancer by activating a series of in-flammatory molecules and signals.Recently,it has been shown that the microbiome also plays an important role in the development and progression of bladder cancer,which can be mediated through the stimulation of chronic inflammation.In effect,the urinary microbiome can play a role in establishing the inflammatory urethral microenvironment that may facilitate the development and progression of bladder cancer.In other words,chronic inflammation caused by the urinary microbiome may promote the initiation and progression of bladder cancer.Here,we provide a detailed and comprehensive account of the link between chronic inflammation,the microbiome and bladder cancer.Finally,we highlight that targeting the urinary microbiome might enable the development of strategies for bladder cancer prevention and personalized treatment.
文摘Non-genetic mechanisms have recently emerged as important drivers of anticancer drug resistance.Among these,the drug tolerant persister(DTP)cell phenotype is attracting more and more attention and giving a predominant non-genetic role in cancer therapy resistance.The DTP phenotype is characterized by a quiescent or slow-cell-cycle reversible state of the cancer cell subpopulation and inert specialization to stimuli,which tolerates anticancer drug exposure to some extent through the interaction of multiple underlying mechanisms and recovering growth and proliferation after drug withdrawal,ultimately leading to treatment resistance and cancer recurrence.Therefore,targeting DTP cells is anticipated to provide new treatment opportunities for cancer patients,although our current knowledge of these DTP cells in treatment resistance remains limited.In this review,we provide a comprehensive overview of the formation characteristics and underlying drug tolerant mechanisms of DTP cells,investigate the potential drugs for DTP(including preclinical drugs,novel use for old drugs,and natural products)based on different medicine models,and discuss the necessity and feasibility of anti-DTP therapy,related application forms,and future issues that will need to be addressed to advance this emerging field towards clinical applications.Nonetheless,understanding the novel functions of DTP cells may enable us to develop new more effective anticancer therapy and improve clinical outcomes for cancer patients.
基金various sources,including Zhejiang Provincial Natural Science Foundation of China(grant No.LQ20H160013,LQ21H160038,and LY23H160026)the Science and Technology Development Fund,Macao SAR(File No.:0098/2021/A2).
文摘Background:Bladder cancer is a highly prevalent and lethal malignant tumor characterized by frequent mutations/deletions of lysine-specific demethylase 6A(KDM6A),which is suggested to be a key event in cancer progression and metastasis.Beta-elemene has been shown to inhibit metastasis and growth of various tumors,but its effect on KDM6A-null bladder cancer cells remains unknown.Objective:This study aimed to investigate the potential and molecular mechanism ofβ-elemene in inhibiting the growth of KDM6A-null bladder cancer.Methods:This study examined the migration ability and viability of RT-4(KDM6A wild-type)and KU19-19(KDM6A-null)cell lines using wound healing assay and CCK-8,respectively.The inhibitory effect ofβ-elemene on KU19-19 cell migration was evaluated using transwell and immunofluorescence assays,and the expression of transfer-related proteins and genes was analyzed through western blot and qRT-PCR,respectively.Molecular docking was performed to predict the targeting ofβ-elemene,and the effects were confirmed in KDM6Aknockdown RT-4 cells.Finally,the therapeutic effect ofβ-elemene on bladder cancer was tested in animal models.Results:The study observed that loss of KDM6A increased bladder cancer cell migration,with KU19-19 exhibiting significantly stronger migration than RT-4.Further investigation revealed thatβ-elemene effectively inhibited KU19-19 cell migration,likely through targeting EZH2 as determined by molecular docking.Overexpression of KDM6A inhibited KU19-19 metastasis,while knockdown of KDM6A in RT-4 cells enhanced cell migration,which was reversed byβ-elemene treatment.Notably,in vivo testing revealed a significant suppression of KU19-19 cell growth withβ-elemene administered at a dosage of 100 mg/kg.Conclusion:β-elemene has the potential to suppress the growth of KDM6A-null bladder cancer by inhibiting epithelial-mesenchymal transition(EMT),which could make it a promising therapeutic option for patients with KDM6A-null bladder cancer.
