Objective:To study the potential of Pituranthos chloranthus essential oil(PC)as a chemoprotective agent.Methods:In the in vitro study,cell proliferation were determined in CT26,SW620,and SW480 cells.Cells were exposed...Objective:To study the potential of Pituranthos chloranthus essential oil(PC)as a chemoprotective agent.Methods:In the in vitro study,cell proliferation were determined in CT26,SW620,and SW480 cells.Cells were exposed to in creasing concentrations of PC(0,6.25,12.5,25,50,100,and 200μg/mL).Combination index was calculated by applying the Chou-Talalay method,apoptopsis was analyzed by annexin V/propidium iodide staining,reactive oxygen species accumulation,and theΔψm drop were also assessed.In the in vivo study,mice were divided into 5 groups:the normal control group,the CT26 tumor-bearing group,the CT26 tumor-bearing mice+PC group,the CT26 tumor-bearing mice+cisplatin group,and the CT26 tumor-bearing mice+cisplatin+PC group.Organ coefficients and tumor volume were calculated.Alanine aminotransferase,aspartate aminotransferase,creatinine,and tumor necrosis factor-αlevels were assessed.Results:Cisplatin with PC induced a synergistic effect,allowing for reduced cisplatin dose while maintaining the same therapeutic efficacy.PC-cisplatin combinations inhibited cell viability by significantly inducing apoptosis,increasing reactive oxygen species accumulation and reducing mitochondrial membrane potential.Co-treatment with cisplatin and PC restored organ coefficients,reduced tumor volume,and alleviated nephrotoxicity in CT26 tumor-bearing mice by restoring kidney function markers and ameliorating kidney inflammation status.Conclusions:PC shows a chemoprotective potential by enhancing the antitumor effect of cisplatin while alleviating its side effects.展开更多
Background:Cisplatin(DDP)has been used in the treatment of various human cancers.However,DDP alone lacks efficacy in treating triple-negative breast cancer(TNBC),and its clinical application is often hampered by side ...Background:Cisplatin(DDP)has been used in the treatment of various human cancers.However,DDP alone lacks efficacy in treating triple-negative breast cancer(TNBC),and its clinical application is often hampered by side effects.Astragalus polysaccharide(APS)is one of the active components extracted from Astragalus membranaceus and has gained attention for its various biological properties.This research is aimed to evaluate the effectiveness of a combination of APS and DDP on TNBC and explore the potential mechanisms.Methods:The efficacy and mechanisms of single or combined treatment were evaluated using Cell Counting Kit-8(CCK8)assay,Annexin V-fluorescein isothiocyanate(FITC)/propidium iodide(PI)staining,wound healing assay,trans-well invasion/migration assay,hematoxylin-eosin(HE)staining,immunohistochemical(IHC)staining,Western Blot(WB)analysis,and fluorescence-activated cell sorting(FACS).An orthotopic model of TNBC was used to assess the in vivo treatment efficacy of single or combination treatment.Results:APS significantly enhanced the anti-proliferative,anti-migratory,and anti-invasive effects of DDP on TNBC cells.The combination of APS and DDP downregulated anti-apoptotic genes(Bcl2 and Bcl-xL)while upregulating pro-apoptotic genes(Puma,Cle-Caspase3,Cle-PARP),leading to enhanced apoptosis.This combination treatment increased E-cadherin levels,decreased Vimentin,Snail,Slug,and Twist levels,and effectively suppressed epithelial-mesenchymal transition(EMT)-associated cell invasion.In the orthotopic model of TNBC,a synergistic reduction in tumor growth was observed in mice treated with APS and DDP.Additionally,the combination of APS and DDP induced the infiltration of CD8+T lymphocytes into the tumor immune microenvironment.Conclusion:The combination of APS and DDP exhibits more potent tumor inhibition and anti-tumor immunity than either agent alone,representing a novel approach to enhance therapeutic efficacy without increasing the side effects of DDP.展开更多
Background:Gallic acid(GA),a plant-derived polyphenol,possesses diverse biological functions such as reducing inflammation and against tumors.Currently,the influence of GA on the resistance of esophageal squamous cell...Background:Gallic acid(GA),a plant-derived polyphenol,possesses diverse biological functions such as reducing inflammation and against tumors.Currently,the influence of GA on the resistance of esophageal squamous cell carcinoma(ESCC)cells to cisplatin(DDP)is not well understood.Methods:Cell counting kit-8 assay examined how GA affected KYSE30 and TE-1 cell viability.5-Ethynyl-2′-deoxyuridine and TdT-mediated dUTP Nick-End labeling staining detected cell proliferation and apoptosis.Clone formation assay,flow cytometry,Carboxyfluorescein diacetate succinimidyl ester fluorescent probes,and Transwell assay determined cell biological properties,and 2′,7′-Dichlorofluorescin diacetate(DCFH-DA)fluorescent probes detected oxidative stress levels.Signal transducer and activator of transcription 3(STAT3)/Notch pathway protein levels after GA and/or Interleukin-6(IL-6)intervention were examined through Western blot.Furthermore,a model for subcutaneous graft tumors was established in nude mice.Results:GA exerted suppressive effects on cell proliferation,and caused apoptosis of KYSE30 and TE-1 cells.IL-6 intervention activated the STAT3/Notch pathway and promoted the malignant biological properties of ESCC cells.In contrast,GA attenuated the effects of IL-6,while STAT3 or Notch inhibitor further enhanced the effects of GA,suggesting that GA inhibited the IL-6/STAT3/Notch pathway.Not only that,GA promoted oxidative stress and enhanced cell sensitivity to DDP both in vitro and in vivo.Conclusion:GA suppresses the malignant progression of ESCC and enhances cell sensitivity to DDP by hindering the IL-6/STAT3/Notch pathway.展开更多
Background:Cisplatin triggers Gasdermin E(GSDME)cleavage,causing membrane bubble formation,content release,and inflammation.Caspase-3 activation initiates GSDME cleavage,and thus inhibiting this pathway mitigates cisp...Background:Cisplatin triggers Gasdermin E(GSDME)cleavage,causing membrane bubble formation,content release,and inflammation.Caspase-3 activation initiates GSDME cleavage,and thus inhibiting this pathway mitigates cisplatin-induced pyroptosis in hepatocytes.This study aimed to delve into how cisplatin induces liver injury via pyroptosis.Methods:For animal experiments,C57BL/6J mice were divided into three groups:control,liver injury model group,and Ac-DMLD-CMK(caspase-3 inhibitor)intervention group.The liver histology was evaluated by hematoxylin and eosin staining,immunohistochemistry,immunofluorescence and TUNEL staining.The mRNA and protein levels were detected by real-time polymerase chain reaction(PCR)and Western blot analysis.For in vitro experiments,HL-7702 cells were treated with cisplatin or GSDME siRNA.Cell pyroptosis was determined via cellular morphology,cytotoxicity and viability detection,flow cytometric assay,and Western blot detection for the expression of pyroptosis-related proteins.Results:Cisplatin-induced distinct liver morphological changes,hepatocellular injury,and inflammation in mice,along with elevated serum alanine aminotransferase(ALT)and aspartate aminotransferase(AST)levels and increased pro-inflammatory cytokine expression.Heightened macrophage infiltration and hepatocellular death indicated cisplatin-induced hepatotoxicity.Cisplatin upregulated GSDME activation,along with Bax-mediated caspase-3 cleavage both in vivo and in vitro,implicating caspase-3/GSDME-dependent pyroptosis in liver injury.Treatment with Ac-DMLD-CMK ameliorated cisplatin-induced liver injury,reducing hepatocellular lesions,serum ALT and AST levels,cytokine expression,macrophage infiltration,and hepatocyte death.Ac-DMLD-CMK also attenuated GSDME-dependent pyroptosis post-cisplatin induction,as evidenced by decreased GSDME expression,Bax upregulation,and cleaved caspase-3 activation.For HL-7702 cells,GSDME siRNA transfection reduced GSDME expression,attenuated typical signs of cisplatin-induced pyroptosis,partially restored cell viability,and significantly inhibited cytotoxicity and a decrease in the proportion of propidium iodide-positive cells,indicating protection against cisplatininduced hepatocyte pyroptosis.Conclusions:Our study underscores the role of the caspase-3/GSDME signaling pathway in mediating cisplatin-induced hepatotoxicity,particularly in cases of excessive or cumulative cisplatin exposure.These findings suggest that targeting GSDME could represent a promising therapeutic approach to mitigate cisplatin-induced liver damage.展开更多
Objectives:Cisplatin(CDDP)therapy for glioblastoma(GBM)is linked with several limitations,which include poor penetration of the blood-brain barrier(BBB),systemic toxicity,and the development of drug resistance mechani...Objectives:Cisplatin(CDDP)therapy for glioblastoma(GBM)is linked with several limitations,which include poor penetration of the blood-brain barrier(BBB),systemic toxicity,and the development of drug resistance mechanisms implicating oxidative stress dysregulation and compromised apoptotic pathways.This study evaluates C-Phycocyanin(C-PC)as a potential adjuvant to enhance CDDP efficacy by modulating redox balance and apoptosis.Methods:GBM cells(U87 and U87-EGFRvIII)were treated with CDDP,C-PC,or their combination.Cell viability was assessed by MTT assay;apoptosis was evaluated by DAPI staining andWestern blot analysis of cleaved Caspase-3 and poly(ADP-ribose)polymerase(PARP).Both intracellular and extracellular reactive oxygen species(ROS)were measured using 2′,7′-dichlorodihydrofluorescein diacetate(DCF-DA)fluorescence and lucigenin chemiluminescence,respectively.Catalase activity was quantified via hydrogen peroxide(H2O2)decomposition assay,and manganese superoxide dismutase(MnSOD)expression byWestern blot.Results:C-PCselectively decreased U87GBMcell viability while sparing normal cells.C-PC enhanced CDDP cytotoxicity,reducing viability to 26.5%vs.53.2%for CDDP alone.This effect correlated with increased apoptosis,evidenced by DNA fragmentation and higher cleaved caspase-3 and PARP levels.Combined treatment lowered ROS below survival thresholds while upregulating MnSOD and catalase activity.In U87-EGFRvIII cells,CDDP reduced viability modestly(85.2%),C-PC alone decreased viability significantly(51.5%)and induced cell death,but the combination did not further increase apoptosis.Here,C-PC’s pro-apoptotic effects,alone or with CDDP,were also associated with reduced oxidative stress in cells.Conclusion:We demonstrate that C-PC enhances CDDP cytotoxicity in sensitive U87 cells by promoting apoptosis and modulating ROS,suggesting potential for improved therapeutic efficacy with reduced systemic toxicity.Compared to the combination,C-PC monotherapy achieves superior cytotoxicity in CDDP-resistant U87-EGFRvIII cells,underscoring its potential as a standalone therapeutic approach for chemotherapy-resistant glioblastoma subtypes.展开更多
Objective:The effectiveness of chemotherapy is affected by tumor heterogeneity and drug resistance mechanisms;however,there are certain limitations.Electroacupuncture can regulate the tumor immune response and restore...Objective:The effectiveness of chemotherapy is affected by tumor heterogeneity and drug resistance mechanisms;however,there are certain limitations.Electroacupuncture can regulate the tumor immune response and restore bone marrow hematopoietic function,which is affected by chemotherapy.This study investigated the efficacy and mechanism of electroacupuncture combined with cisplatin in the treatment of non-small-cell lung cancer mice.Methods:To establish a mouse model of non-small-cell lung cancer,gene sequencing combined with bioinformatics analysis,flow cytometry,and liquid-phase chips was used to observe the expression of immune cells and related factors in the mouse tumor microenvironment.Flow cytometry was used to observe subpopulations of mouse bone marrow hematopoietic stem cells and progenitor cells.PAC1 receptor agonists were used to observe mouse tumor immunity and bone marrow hematopoiesis-related indicators.Results:The combination of electroacupuncture with high-and low-dose chemotherapy had a better tumor-suppressive effect.Electroacupuncture can affect the gene expression profile of immune cells,especially the expression levels of Ccr1,Cxcr5,Zbp1,and CamkIIα,and increases the levels of interferon-γ(IFN-γ)and interleukin(IL)-2 protein,upregulating the levels of cytokines Ccl4,Ccl3,and IL-6 in the tumor tissue.Additionally,electroacupuncture enhanced the infiltration of CD8+T cells,dendritic cells,and M1-type macrophages at the tumor site,and reduced the proportion of Th17 and Treg cells.Furthermore,electroacupuncture remodels the bone marrow hematopoietic microenvironment after chemotherapy by increasing the number of bone marrow hematopoietic stem cell subsets,leukocytes,and subpopulations in the peripheral blood.PAC1 receptor agonists have similar effects to those of electroacupuncture on hematopoietic protection and tumor immunity after chemotherapy.Conclusions:Electroacupuncture may improve chemotherapy-induced bone marrow suppression,reshape the tumor microenvironment immune response affected by chemotherapy,and change the tumor immune microenvironment to an anti-tumor mode by regulating tumor local immune-related cytokines.The PAC1 receptor may be a drug target for the treatment of myelosuppression and immunosuppression in patients with tumors.展开更多
BACKGROUND Intrahepatic cholangiocarcinoma(iCCA)is the second most common liver malignancy with poor prognosis and limited treatment options.AIM To identify the most effective drug for transarterial chemoembolization(...BACKGROUND Intrahepatic cholangiocarcinoma(iCCA)is the second most common liver malignancy with poor prognosis and limited treatment options.AIM To identify the most effective drug for transarterial chemoembolization(TACE)in cholangiocarcinoma and evaluate the efficacy and safety of combining it with gemcitabine and cisplatin(GemCis)for unresectable iCCA.METHODS Cholangiocarcinoma cell lines(RBE,HuCC-T1)were treated with 10 chemotherapeutic drugs,and cytotoxicity was assessed by cell counting kit-8 assays.Tumorbearing nude mice were treated with idarubicin or GemCis,and tumor growth was monitored.Clinical data from 85 iCCA patients were analyzed to evaluate the efficacy and safety of idarubicin-TACE combined with GemCis.RESULTS Idarubicin demonstrated the highest cytotoxicity,significantly outperforming GemCis,the standard first-line therapies.In tumor-bearing mouse models,idarubicin and GemCis treatments significantly slowed tumor growth,with idarubicin showing particularly pronounced effects on days 12 and 15(P<0.05).In retrospective analysis,the median overall survival(OS)and progression-free survival(PFS)in the combination therapy group were significantly longer than those in the GemCis alone group(median OS,16.23 months vs 10.07 months,P=0.042;median PFS,7.73 months vs 6.30 months,P=0.023).Additionally,major grade 3/4 adverse events(AEs)in the combination therapy group were abdominal pain(26.3%vs 6.5%,P=0.049)and elevated transaminases(42.1%vs 12.9%,P=0.038).Most AEs were mild to moderate and manageable.CONCLUSION Idarubicin demonstrated higher cytotoxicity than GemCis,significantly inhibiting tumor growth in tumor-bearing mouse models.Preliminary clinical results suggest that local idarubicin-TACE combined with GemCis may offer improved survival outcomes for iCCA patients with a manageable safety profile.展开更多
Background:Cisplatin(CDDP)is a cornerstone chemotherapeutic agent for many solid tumors,but its clinical use is severely limited by dose-dependent nephrotoxicity,which results in acute kidney injury(AKI)in a significa...Background:Cisplatin(CDDP)is a cornerstone chemotherapeutic agent for many solid tumors,but its clinical use is severely limited by dose-dependent nephrotoxicity,which results in acute kidney injury(AKI)in a significant proportion of patients.CDDP-induced AKI involves interconnected mechanisms,including inflammation,oxidative stress,and tubular cell death.In this study,we aimed to investigate the renoprotective effects of esculetin(ES),a natural antioxidant coumarin,in a murine model of CDDP-induced AKI.Methods:Male C57BL/6 mice(8–10 weeks)received a single intraperitoneal injection of CDDP(20 mg/kg)with or without ES(40 mg/kg/day,oral gavage).Renal function,histopathology,and molecular markers of inflammation,oxidative stress,mitogen-activated protein kinase(MAPK)activation,endoplasmic reticulum(ER)stress,apoptosis,and ferroptosis were assessed by standard biochemical,histological,and immunoblotting techniques.Results:ES significantly reduced CDDP-induced elevations in serum creatinine and blood urea nitrogen,preserved renal structure,and decreased histological injury scores.Molecular analyses showed that ES suppressed the production of systemic and renal proinflammatory cytokines and inhibited the expression of chemokines and adhesion molecules.ES also suppressed the phosphorylation of extracellular signal-regulated kinase 1/2 and p38 MAPKs,mitigating stress-induced inflammatory and apoptotic signaling.Additionally,ES treatment reduced the expression of unfolded protein response markers,such as C/EBP homologous protein,which is indicative of alleviated ER stress.Oxidative injury was reduced,as evidenced by lower malondialdehyde and 4-hydroxynonenal levels and restored glutathione content.Importantly,ES mitigated ferroptosis,as demonstrated by decreased expression of pro-ferroptotic markers and preservation of anti-ferroptotic mediators,including glutathione peroxidase 4 and solute carrier family 7member 1.Conclusion:Collectively,our findings provide the first in vivo evidence that ES robustly protects against CDDP-induced AKI by simultaneously targeting oxidative stress,inflammation,MAPK,and ER stress pathways,apoptosis,and ferroptosis.These results highlight ES as a potential candidate for preventing CDDP-induced nephrotoxicity.展开更多
Liposomal drugs have significantly improved cancer treatment in recent years.However,the clinical application of conventional liposomes is limited by factors such as the complexity of the preparation process and the m...Liposomal drugs have significantly improved cancer treatment in recent years.However,the clinical application of conventional liposomes is limited by factors such as the complexity of the preparation process and the multitude of auxiliary components.By replacing phospholipids and cholesterol with vitamin E succinate(VES),this study addresses these shortcomings by developing a novel modified nanoprodrug,and the new formulation is used to deliver cisplatin.Concurrently,liposomes encapsulating cisplatin were prepared by conventional formulations for comparative experiments.Moreover,VES can inhibit the expression of mitochondrial uncoupling protein 2(UCP2),further enhancing mitochondrial damage in tumor cells within the tumor microenvironment(TME)and suppressing the tricarboxylic acid cycle,thereby reducing ATP production.Additionally,cisplatin damages DNA structure,affecting the binding of Nrf2 to the antioxidant response element(ARE),thereby inhibiting the signaling expression of heme oxygenase1(HO-1).The combined action of cisplatin and VES disrupts the redox balanceleading to a significant accumulation of reactive oxygen species(ROS).The nanoprodrug effectively alters the redox state of the TME and inhibits antioxidant defenses,thereby amplifying oxidative stress damage and enhancing the efficacy of cisplatin.Notably,compared to free cisplatin,the nanoprodrug demonstrates greater efficacy in both cell line-derived xenograft(CDX)and patient-derived tumor xenograft(PDX)liver cancer models.Overall,this study successfully develops a novel mitochondrial-targeted nanoprodrug by modifying the conventional liposome formulation.This provides a new strategy for amplifying oxidative stress in order to disrupt redox balance,and enhance cisplatin efficacy.展开更多
[Objectives]To investigate whether Ailanthone(AIL)could reverse cisplatin resistance in non-small cell lung cancer(NSCLC)by modulating autophagy pathways in A549/DDP cells.[Methods]Cisplatin-resistant A549/DDP cells w...[Objectives]To investigate whether Ailanthone(AIL)could reverse cisplatin resistance in non-small cell lung cancer(NSCLC)by modulating autophagy pathways in A549/DDP cells.[Methods]Cisplatin-resistant A549/DDP cells were treated with AIL(0.6μmol/L),cisplatin(50μg/mL),or their combination.Cell proliferation was assessed by MTT,EdU and colony formation assays;migration by Transwell and wound healing assays;autophagy markers(P62,LC3B,Beclin1,ATG5)by Western blot;LC3B puncta by immunofluorescence;with rescue experiments using rapamycin.[Results]The AIL-cisplatin combination synergistically inhibited proliferation and migration,while downregulating P-gp and MVP.AIL significantly increased P62 accumulation while decreasing LC3B-II,Beclin1 and ATG5.Rapamycin reversed these effects,restoring viability and resistance markers.[Conclusions]AIL reverses cisplatin resistance in NSCLC by inhibiting autophagy through P62/LC3B regulation,offering a promising therapeutic strategy for refractory NSCLC.展开更多
Cisplatin chemotherapy has been used as the main treatment for different types of cancer.However,cisplatin chemotherapy-induced peripheral neuropathic pain(CIPNP)seriously affects the treatment process and quality of ...Cisplatin chemotherapy has been used as the main treatment for different types of cancer.However,cisplatin chemotherapy-induced peripheral neuropathic pain(CIPNP)seriously affects the treatment process and quality of life of patients.In addition,it impacts the underlying mechanism and prevention and treatment strategies,indicating that drug selection and efficacy evaluation need to be further investigated.Furthermore,an animal model that is more consistent with the pathological mechanism needs to be developed.In this study,we describe and discuss the methods of developing and detecting CIPNP models in rats and mice induced by cisplatin chemotherapy.The aim was to improve the modeling rate and develop animal models that are more consistent with the developmental pattern of the disease.In addition,the study provides ideal reference animal models for clinical research and drug discovery and development.展开更多
Chemoresistance remains a major challenge in non-small cell lung cancer,especially for cisplatin(DDP)-based therapies,which are a mainstay of treatment.In their study,Dai et al investigate how inflammatory cytokines w...Chemoresistance remains a major challenge in non-small cell lung cancer,especially for cisplatin(DDP)-based therapies,which are a mainstay of treatment.In their study,Dai et al investigate how inflammatory cytokines within the tumor microenvironment contribute to DDP resistance.By analyzing tumor samples from 20 non-small cell lung cancer patients and two resistant cell lines(A549/DDP and SK-MES-1/DDP),the authors show that increased levels of interleukin(IL)-6,IL-8,and tumor necrosis factor-αare linked to resistance.Logistic regression identifies IL-6 and IL-8 as key risk factors.Functional experiments using tocilizumab,an IL-6 receptor antagonist,demonstrate a reduction in DDP half maximum inhibitory concentration,higher apoptosis rates,and decreased migration and invasion in resistant cells.Although the study has certain limitations,such as the analysis of only five inflammatory cytokines in a small,non-stratified patient cohort;it demonstrates that targeting the IL-6 cytokine axis may help overcome DDP resistance.Overall,the study highlights the inflammatory component of the tumor microenvironment as a modifiable driver of chemoresistance and provide a rationale for integrating cytokine blockade into platinum-based chemotherapy regimens to enhance therapeutic response.展开更多
BACKGROUND As a member of the chaperonin-containing tailless complex polypeptide 1(TCP1)complex,which plays a pivotal role in ensuring the accurate folding of numerous proteins,chaperonin-containing TCP1 subunit 6A(CC...BACKGROUND As a member of the chaperonin-containing tailless complex polypeptide 1(TCP1)complex,which plays a pivotal role in ensuring the accurate folding of numerous proteins,chaperonin-containing TCP1 subunit 6A(CCT6A)participates in various physiological and pathological processes.However,its effects on cell death and cancer therapy and the underlying mechanisms need further exploration in colorectal cancer(CRC)cells.AIM To explore the effects of CCT6A on cell death and cancer therapy and the underlying mechanisms in CRC.METHODS Cell proliferation was evaluated using the MTS assay,EdU staining,and colony growth assays.The expression of CCT6A was monitored by immunoblotting and quantitative PCR.CCT6A was knocked out by CRISPR-Cas9,and overexpressed by transfecting plasmids.Autophagy was examined by immunoblotting and the mCherry-GFP-LC3 assay.To monitor apoptosis and necroptosis,immunoblotting,co-immunoprecipitation,and flow cytometry were employed.RESULTS Cisplatin(DDP)exerted cytotoxic effects on CRC cells while simultaneously downregulating the expression of CCT6A.Depletion of CCT6A amplified the cytotoxic effects of DDP,whereas overexpression of CCT6A attenuated these adverse effects.CCT6A suppressed autophagy,apoptosis,and necroptosis under both basal and DDP-treated conditions.Autophagy inhibitors significantly enhanced the cytotoxic effects of DDP,whereas a necroptosis inhibitor partially reversed the cell viability loss induced by DDP.Furthermore,inhibiting autophagy enhanced both apoptosis and necroptosis induced by DDP.CONCLUSION CCT6A negatively modulates autophagy,apoptosis,and necroptosis,and CCT6A confers resistance to DDP therapy in CRC,suggesting its potential as a therapeutic target.展开更多
Background:Despite the identification of numerous therapeutic targets in lung cancer,achieving significant efficacy has been challenging.TNFRSF21 plays an important role in various cancers.We investigated the function...Background:Despite the identification of numerous therapeutic targets in lung cancer,achieving significant efficacy has been challenging.TNFRSF21 plays an important role in various cancers.We investigated the function of TNFRSF21 in lung adenocarcinoma(LUAD).Methods:The prognostic value of TNFRSF21 expression in lung cancer was evaluated by the GEPIA and Kaplan-Meier Plotter databases.Lung cancer cell viability was assessed by the CCK8 assay.TNFRSF21 expression patterns in lung cancer tissues and cells were examined using RT-PCR assay.Tumor sphere growth was evaluated through tumor sphere formation assays.MtROS contents in lung cancer cells were observed through MitoSOX fluorescent assays.Result:TNFRSF21 was up-regulated in LUAD patients.TNFRSF21 induction was particularly notable in LUAD,especially in cancerous cells(A549,H1299,H460,and SPC-A1),compared to BEAS-2B cells.Additionally,TNFRSF21 was increased in cisplatin(DDP)-resistant LUAD cells.Loss of TNFRSF21 significantly inhibited LUAD cell growth.It was observed that forced expression of TNFRSF21 contributed to tumor cell proliferation and DDP resistance.The production of ROS was found to participate in the inhibitory effects on lung cancer stem cells(CSCs),with decreased TNFRSF21 restraining ROS contents.Collectively,these findings reveal that the downregulation of TNFRSF21 promotes ROS contents to restrain the lung CSC-like characteristics via modulation of CD44 and CD133.Conclusions:In conclusion,TNFRSF21 may act as a novel target for lung cancer chemotherapy,particularly for eradicating lung CSCs.展开更多
The published article titled“Overexpression of the Long Noncoding RNA FOXD2-AS1 Promotes Cisplatin Resistance in Esophageal Squamous Cell Carcinoma Through the miR-195/Akt/mTOR Axis”has been retracted from Oncology ...The published article titled“Overexpression of the Long Noncoding RNA FOXD2-AS1 Promotes Cisplatin Resistance in Esophageal Squamous Cell Carcinoma Through the miR-195/Akt/mTOR Axis”has been retracted from Oncology Research,Vol.28,No.1,2020,pp.65-73.展开更多
The interaction of cisplatin and its analogues with phospholipid molecules of hu-man erythrocyte membranes was studied using IR and ￣31 P NMR methods. Dramatic changes were ob-served at 1300～953 cm￣-1 frequency reg...The interaction of cisplatin and its analogues with phospholipid molecules of hu-man erythrocyte membranes was studied using IR and ￣31 P NMR methods. Dramatic changes were ob-served at 1300～953 cm￣-1 frequency region on the IR spectra .Based on the IR data analysis, it was speculated that the Pt(II) complexes interacted mainly with the polar head groups of phospholipids through electrostatic interaction and certain coordination patterns. The 1 2 h dynamic experiment showed that a recoverable process occurred in case of cis-DCDP and an unrecoverable one for other pt(II)analogues.A similar conclusion could be obtained from￣31 P NMR experimental results.The di-versity was discussed.展开更多
The antitumor activities of ethaselen （BBSKE） in combination with cisplatin （CDDP） in vitro have been investigated in human stomach cancer cell line BGC 823 and human lung cancer cell line PG-BE1. MTT method was u...The antitumor activities of ethaselen （BBSKE） in combination with cisplatin （CDDP） in vitro have been investigated in human stomach cancer cell line BGC 823 and human lung cancer cell line PG-BE1. MTT method was used to assess the individual effects of ethaselen and cisplatin and their combined effects on cell proliferation of BGC 823 cells and PG-BE1 cells. Additionally, we used the classic median effect theory to calculate the combination index （CI） of ethaselen and cisplatin with different dose regimes in combination, and compared the effective dosages of cisplatin in individual treatment and combination treatment. When ethaselen and cisplatin were used in combination, a synergistic effect was observed. The most remarkable synergistic effect was observed when the dose ratio of cisplatin to ethaselen was 2：3 in BGC 823 cell line and 1：3 in PG-BE1 cell line. The dose of cisplatin could be decreased markedly in combination group to reach the same inhibitory effect, and this effect was gradually raised with the increase of the concentration of drugs.展开更多
It has been reported that Ethaselen shows inhibitory effects on thioredoxin reductase（TrxR） activity and human tumor cell growth. In order to find an efficient way to reverse cisplatin resistance, we investigated th...It has been reported that Ethaselen shows inhibitory effects on thioredoxin reductase（TrxR） activity and human tumor cell growth. In order to find an efficient way to reverse cisplatin resistance, we investigated the reversal effects of Ethaselen on cisplatin resistance in K562/cisplatin（CDDP） cells that were established by pulse-inducing human erythrocyte leukemic cell line K562, which are fivefold more resistant to cisplatin compared to K562 cells. The morphology and growth showed that the adhesion of K562/CDDP further decreased while the cell volume increased. The proliferation of K562/CDDP is strengthened. The antitumor activities in vitro were assessed by MTT（3-（4,5-dimethylthiazol-2-yl）-2,5-diphenyltetrazolium bromide） assay and combination index（CI）, showing the significant synergic effects of cisplatin and Ethaselen. Focusing on apoptosis, a series of comparisons was made between K562 and K562/CDDP. Cisplatin induced higher reactive oxygen species（ROS） generation in K562 and subsequently induced the formation of mitochondrial permeability transition pores（PTPs）. In addition, cisplatin increased the ratio of Bax to Bcl-2 in K562, which can influence the mitochondrial membrane permeability. PTP formation and mitochondrial membrane permeabilization eventually resulted in the release of cytochrome c and activation of the Caspase pathway. However, these effects were not clearly seen in K562/CDDP, which may be the reason for the acquired CDDP resistance. However, Ethaselen can induce a high level of ROS in K562/CDDP by TrxR activity inhibition and increased ratio of Bax to Bcl-2 in K562/CDDP by nuclear factor κB（NF-κB） suppression, which subsequently induces the release of cytochrome c in K562/CDDP. This response is partly responsible for the reversal of the cisplatin resistance in K562/CDDP cells.展开更多
The interaction between cisplatin and erythrocyte membrane proteins was studied based on the quenching effect of cisplatin on the intrinsic fluorescence of proteins.A concentration-dependent quenching effect was obser...The interaction between cisplatin and erythrocyte membrane proteins was studied based on the quenching effect of cisplatin on the intrinsic fluorescence of proteins.A concentration-dependent quenching effect was observed.The presence of chloride and sulphate weakens the effect significantly.A pH-dependence was also noted with a stronger effect in acidic solution. The nature of the interaction is considered to be platinum-thiol group binding according to the effect of cisplatin on the fluorescence of FMA labeled membrane. The mechanism of the cisplatin-protein interactions was discussed based on the effect of coexisting anion展开更多
Acute Kidney Injury (AKI) is a condition that causes nephrotoxicity in kidney tissues due to cisplatin-induced cancer treatments. Hence, it is proposed in this review that AVE0991 (a MAS-receptor Angiotensin II (1-7) ...Acute Kidney Injury (AKI) is a condition that causes nephrotoxicity in kidney tissues due to cisplatin-induced cancer treatments. Hence, it is proposed in this review that AVE0991 (a MAS-receptor Angiotensin II (1-7) agonist) may reduce cisplatin-induced acute kidney injury by promoting nitric oxide production.展开更多
基金funded by The Tunisian Ministry of Research and Higher Education.
文摘Objective:To study the potential of Pituranthos chloranthus essential oil(PC)as a chemoprotective agent.Methods:In the in vitro study,cell proliferation were determined in CT26,SW620,and SW480 cells.Cells were exposed to in creasing concentrations of PC(0,6.25,12.5,25,50,100,and 200μg/mL).Combination index was calculated by applying the Chou-Talalay method,apoptopsis was analyzed by annexin V/propidium iodide staining,reactive oxygen species accumulation,and theΔψm drop were also assessed.In the in vivo study,mice were divided into 5 groups:the normal control group,the CT26 tumor-bearing group,the CT26 tumor-bearing mice+PC group,the CT26 tumor-bearing mice+cisplatin group,and the CT26 tumor-bearing mice+cisplatin+PC group.Organ coefficients and tumor volume were calculated.Alanine aminotransferase,aspartate aminotransferase,creatinine,and tumor necrosis factor-αlevels were assessed.Results:Cisplatin with PC induced a synergistic effect,allowing for reduced cisplatin dose while maintaining the same therapeutic efficacy.PC-cisplatin combinations inhibited cell viability by significantly inducing apoptosis,increasing reactive oxygen species accumulation and reducing mitochondrial membrane potential.Co-treatment with cisplatin and PC restored organ coefficients,reduced tumor volume,and alleviated nephrotoxicity in CT26 tumor-bearing mice by restoring kidney function markers and ameliorating kidney inflammation status.Conclusions:PC shows a chemoprotective potential by enhancing the antitumor effect of cisplatin while alleviating its side effects.
基金the Xuzhou Science and Technology Bureau,No.KC23186,Jiangsu Provincial Key Laboratory of New Drug Research and Clinical Pharmacy Project(No.XZSYSKF2023013)Key Medical Disciplines of Jiangsu Province’s 14th Five-Year Plan(ZDXK202237).
文摘Background:Cisplatin(DDP)has been used in the treatment of various human cancers.However,DDP alone lacks efficacy in treating triple-negative breast cancer(TNBC),and its clinical application is often hampered by side effects.Astragalus polysaccharide(APS)is one of the active components extracted from Astragalus membranaceus and has gained attention for its various biological properties.This research is aimed to evaluate the effectiveness of a combination of APS and DDP on TNBC and explore the potential mechanisms.Methods:The efficacy and mechanisms of single or combined treatment were evaluated using Cell Counting Kit-8(CCK8)assay,Annexin V-fluorescein isothiocyanate(FITC)/propidium iodide(PI)staining,wound healing assay,trans-well invasion/migration assay,hematoxylin-eosin(HE)staining,immunohistochemical(IHC)staining,Western Blot(WB)analysis,and fluorescence-activated cell sorting(FACS).An orthotopic model of TNBC was used to assess the in vivo treatment efficacy of single or combination treatment.Results:APS significantly enhanced the anti-proliferative,anti-migratory,and anti-invasive effects of DDP on TNBC cells.The combination of APS and DDP downregulated anti-apoptotic genes(Bcl2 and Bcl-xL)while upregulating pro-apoptotic genes(Puma,Cle-Caspase3,Cle-PARP),leading to enhanced apoptosis.This combination treatment increased E-cadherin levels,decreased Vimentin,Snail,Slug,and Twist levels,and effectively suppressed epithelial-mesenchymal transition(EMT)-associated cell invasion.In the orthotopic model of TNBC,a synergistic reduction in tumor growth was observed in mice treated with APS and DDP.Additionally,the combination of APS and DDP induced the infiltration of CD8+T lymphocytes into the tumor immune microenvironment.Conclusion:The combination of APS and DDP exhibits more potent tumor inhibition and anti-tumor immunity than either agent alone,representing a novel approach to enhance therapeutic efficacy without increasing the side effects of DDP.
基金Mechanistic Investigation into the Extraction,Purification,and Anti-Esophageal Cancer Effects of Gallic Acid Derived from Rhodiola crenulata(YLUKLM2023001).
文摘Background:Gallic acid(GA),a plant-derived polyphenol,possesses diverse biological functions such as reducing inflammation and against tumors.Currently,the influence of GA on the resistance of esophageal squamous cell carcinoma(ESCC)cells to cisplatin(DDP)is not well understood.Methods:Cell counting kit-8 assay examined how GA affected KYSE30 and TE-1 cell viability.5-Ethynyl-2′-deoxyuridine and TdT-mediated dUTP Nick-End labeling staining detected cell proliferation and apoptosis.Clone formation assay,flow cytometry,Carboxyfluorescein diacetate succinimidyl ester fluorescent probes,and Transwell assay determined cell biological properties,and 2′,7′-Dichlorofluorescin diacetate(DCFH-DA)fluorescent probes detected oxidative stress levels.Signal transducer and activator of transcription 3(STAT3)/Notch pathway protein levels after GA and/or Interleukin-6(IL-6)intervention were examined through Western blot.Furthermore,a model for subcutaneous graft tumors was established in nude mice.Results:GA exerted suppressive effects on cell proliferation,and caused apoptosis of KYSE30 and TE-1 cells.IL-6 intervention activated the STAT3/Notch pathway and promoted the malignant biological properties of ESCC cells.In contrast,GA attenuated the effects of IL-6,while STAT3 or Notch inhibitor further enhanced the effects of GA,suggesting that GA inhibited the IL-6/STAT3/Notch pathway.Not only that,GA promoted oxidative stress and enhanced cell sensitivity to DDP both in vitro and in vivo.Conclusion:GA suppresses the malignant progression of ESCC and enhances cell sensitivity to DDP by hindering the IL-6/STAT3/Notch pathway.
基金supported by grants from the National Natural Science Foundation of China(8170060495 and 82170682)。
文摘Background:Cisplatin triggers Gasdermin E(GSDME)cleavage,causing membrane bubble formation,content release,and inflammation.Caspase-3 activation initiates GSDME cleavage,and thus inhibiting this pathway mitigates cisplatin-induced pyroptosis in hepatocytes.This study aimed to delve into how cisplatin induces liver injury via pyroptosis.Methods:For animal experiments,C57BL/6J mice were divided into three groups:control,liver injury model group,and Ac-DMLD-CMK(caspase-3 inhibitor)intervention group.The liver histology was evaluated by hematoxylin and eosin staining,immunohistochemistry,immunofluorescence and TUNEL staining.The mRNA and protein levels were detected by real-time polymerase chain reaction(PCR)and Western blot analysis.For in vitro experiments,HL-7702 cells were treated with cisplatin or GSDME siRNA.Cell pyroptosis was determined via cellular morphology,cytotoxicity and viability detection,flow cytometric assay,and Western blot detection for the expression of pyroptosis-related proteins.Results:Cisplatin-induced distinct liver morphological changes,hepatocellular injury,and inflammation in mice,along with elevated serum alanine aminotransferase(ALT)and aspartate aminotransferase(AST)levels and increased pro-inflammatory cytokine expression.Heightened macrophage infiltration and hepatocellular death indicated cisplatin-induced hepatotoxicity.Cisplatin upregulated GSDME activation,along with Bax-mediated caspase-3 cleavage both in vivo and in vitro,implicating caspase-3/GSDME-dependent pyroptosis in liver injury.Treatment with Ac-DMLD-CMK ameliorated cisplatin-induced liver injury,reducing hepatocellular lesions,serum ALT and AST levels,cytokine expression,macrophage infiltration,and hepatocyte death.Ac-DMLD-CMK also attenuated GSDME-dependent pyroptosis post-cisplatin induction,as evidenced by decreased GSDME expression,Bax upregulation,and cleaved caspase-3 activation.For HL-7702 cells,GSDME siRNA transfection reduced GSDME expression,attenuated typical signs of cisplatin-induced pyroptosis,partially restored cell viability,and significantly inhibited cytotoxicity and a decrease in the proportion of propidium iodide-positive cells,indicating protection against cisplatininduced hepatocyte pyroptosis.Conclusions:Our study underscores the role of the caspase-3/GSDME signaling pathway in mediating cisplatin-induced hepatotoxicity,particularly in cases of excessive or cumulative cisplatin exposure.These findings suggest that targeting GSDME could represent a promising therapeutic approach to mitigate cisplatin-induced liver damage.
文摘Objectives:Cisplatin(CDDP)therapy for glioblastoma(GBM)is linked with several limitations,which include poor penetration of the blood-brain barrier(BBB),systemic toxicity,and the development of drug resistance mechanisms implicating oxidative stress dysregulation and compromised apoptotic pathways.This study evaluates C-Phycocyanin(C-PC)as a potential adjuvant to enhance CDDP efficacy by modulating redox balance and apoptosis.Methods:GBM cells(U87 and U87-EGFRvIII)were treated with CDDP,C-PC,or their combination.Cell viability was assessed by MTT assay;apoptosis was evaluated by DAPI staining andWestern blot analysis of cleaved Caspase-3 and poly(ADP-ribose)polymerase(PARP).Both intracellular and extracellular reactive oxygen species(ROS)were measured using 2′,7′-dichlorodihydrofluorescein diacetate(DCF-DA)fluorescence and lucigenin chemiluminescence,respectively.Catalase activity was quantified via hydrogen peroxide(H2O2)decomposition assay,and manganese superoxide dismutase(MnSOD)expression byWestern blot.Results:C-PCselectively decreased U87GBMcell viability while sparing normal cells.C-PC enhanced CDDP cytotoxicity,reducing viability to 26.5%vs.53.2%for CDDP alone.This effect correlated with increased apoptosis,evidenced by DNA fragmentation and higher cleaved caspase-3 and PARP levels.Combined treatment lowered ROS below survival thresholds while upregulating MnSOD and catalase activity.In U87-EGFRvIII cells,CDDP reduced viability modestly(85.2%),C-PC alone decreased viability significantly(51.5%)and induced cell death,but the combination did not further increase apoptosis.Here,C-PC’s pro-apoptotic effects,alone or with CDDP,were also associated with reduced oxidative stress in cells.Conclusion:We demonstrate that C-PC enhances CDDP cytotoxicity in sensitive U87 cells by promoting apoptosis and modulating ROS,suggesting potential for improved therapeutic efficacy with reduced systemic toxicity.Compared to the combination,C-PC monotherapy achieves superior cytotoxicity in CDDP-resistant U87-EGFRvIII cells,underscoring its potential as a standalone therapeutic approach for chemotherapy-resistant glioblastoma subtypes.
基金supported by the National Key Research and Development Program of China(2022YFC3500404)the Natural Science Foundation of China(NSFC)(81704146,82205310)+1 种基金the Research Program Project of Tianjin Education Commission(2021KJ120)the National College Student Innovation and Entrepreneurship Training Program(202410063009)。
文摘Objective:The effectiveness of chemotherapy is affected by tumor heterogeneity and drug resistance mechanisms;however,there are certain limitations.Electroacupuncture can regulate the tumor immune response and restore bone marrow hematopoietic function,which is affected by chemotherapy.This study investigated the efficacy and mechanism of electroacupuncture combined with cisplatin in the treatment of non-small-cell lung cancer mice.Methods:To establish a mouse model of non-small-cell lung cancer,gene sequencing combined with bioinformatics analysis,flow cytometry,and liquid-phase chips was used to observe the expression of immune cells and related factors in the mouse tumor microenvironment.Flow cytometry was used to observe subpopulations of mouse bone marrow hematopoietic stem cells and progenitor cells.PAC1 receptor agonists were used to observe mouse tumor immunity and bone marrow hematopoiesis-related indicators.Results:The combination of electroacupuncture with high-and low-dose chemotherapy had a better tumor-suppressive effect.Electroacupuncture can affect the gene expression profile of immune cells,especially the expression levels of Ccr1,Cxcr5,Zbp1,and CamkIIα,and increases the levels of interferon-γ(IFN-γ)and interleukin(IL)-2 protein,upregulating the levels of cytokines Ccl4,Ccl3,and IL-6 in the tumor tissue.Additionally,electroacupuncture enhanced the infiltration of CD8+T cells,dendritic cells,and M1-type macrophages at the tumor site,and reduced the proportion of Th17 and Treg cells.Furthermore,electroacupuncture remodels the bone marrow hematopoietic microenvironment after chemotherapy by increasing the number of bone marrow hematopoietic stem cell subsets,leukocytes,and subpopulations in the peripheral blood.PAC1 receptor agonists have similar effects to those of electroacupuncture on hematopoietic protection and tumor immunity after chemotherapy.Conclusions:Electroacupuncture may improve chemotherapy-induced bone marrow suppression,reshape the tumor microenvironment immune response affected by chemotherapy,and change the tumor immune microenvironment to an anti-tumor mode by regulating tumor local immune-related cytokines.The PAC1 receptor may be a drug target for the treatment of myelosuppression and immunosuppression in patients with tumors.
基金Supported by the Guangzhou Science and Technology Plan Project,No.2023A04J0419National Natural Science Foundation Cultivation Project at the Third Affiliated Hospital of Sun Yat-sen University,No.2022GZRPYQN04.
文摘BACKGROUND Intrahepatic cholangiocarcinoma(iCCA)is the second most common liver malignancy with poor prognosis and limited treatment options.AIM To identify the most effective drug for transarterial chemoembolization(TACE)in cholangiocarcinoma and evaluate the efficacy and safety of combining it with gemcitabine and cisplatin(GemCis)for unresectable iCCA.METHODS Cholangiocarcinoma cell lines(RBE,HuCC-T1)were treated with 10 chemotherapeutic drugs,and cytotoxicity was assessed by cell counting kit-8 assays.Tumorbearing nude mice were treated with idarubicin or GemCis,and tumor growth was monitored.Clinical data from 85 iCCA patients were analyzed to evaluate the efficacy and safety of idarubicin-TACE combined with GemCis.RESULTS Idarubicin demonstrated the highest cytotoxicity,significantly outperforming GemCis,the standard first-line therapies.In tumor-bearing mouse models,idarubicin and GemCis treatments significantly slowed tumor growth,with idarubicin showing particularly pronounced effects on days 12 and 15(P<0.05).In retrospective analysis,the median overall survival(OS)and progression-free survival(PFS)in the combination therapy group were significantly longer than those in the GemCis alone group(median OS,16.23 months vs 10.07 months,P=0.042;median PFS,7.73 months vs 6.30 months,P=0.023).Additionally,major grade 3/4 adverse events(AEs)in the combination therapy group were abdominal pain(26.3%vs 6.5%,P=0.049)and elevated transaminases(42.1%vs 12.9%,P=0.038).Most AEs were mild to moderate and manageable.CONCLUSION Idarubicin demonstrated higher cytotoxicity than GemCis,significantly inhibiting tumor growth in tumor-bearing mouse models.Preliminary clinical results suggest that local idarubicin-TACE combined with GemCis may offer improved survival outcomes for iCCA patients with a manageable safety profile.
基金supported by research grants from Daegu Catholic University in 2024(No.20245001).
文摘Background:Cisplatin(CDDP)is a cornerstone chemotherapeutic agent for many solid tumors,but its clinical use is severely limited by dose-dependent nephrotoxicity,which results in acute kidney injury(AKI)in a significant proportion of patients.CDDP-induced AKI involves interconnected mechanisms,including inflammation,oxidative stress,and tubular cell death.In this study,we aimed to investigate the renoprotective effects of esculetin(ES),a natural antioxidant coumarin,in a murine model of CDDP-induced AKI.Methods:Male C57BL/6 mice(8–10 weeks)received a single intraperitoneal injection of CDDP(20 mg/kg)with or without ES(40 mg/kg/day,oral gavage).Renal function,histopathology,and molecular markers of inflammation,oxidative stress,mitogen-activated protein kinase(MAPK)activation,endoplasmic reticulum(ER)stress,apoptosis,and ferroptosis were assessed by standard biochemical,histological,and immunoblotting techniques.Results:ES significantly reduced CDDP-induced elevations in serum creatinine and blood urea nitrogen,preserved renal structure,and decreased histological injury scores.Molecular analyses showed that ES suppressed the production of systemic and renal proinflammatory cytokines and inhibited the expression of chemokines and adhesion molecules.ES also suppressed the phosphorylation of extracellular signal-regulated kinase 1/2 and p38 MAPKs,mitigating stress-induced inflammatory and apoptotic signaling.Additionally,ES treatment reduced the expression of unfolded protein response markers,such as C/EBP homologous protein,which is indicative of alleviated ER stress.Oxidative injury was reduced,as evidenced by lower malondialdehyde and 4-hydroxynonenal levels and restored glutathione content.Importantly,ES mitigated ferroptosis,as demonstrated by decreased expression of pro-ferroptotic markers and preservation of anti-ferroptotic mediators,including glutathione peroxidase 4 and solute carrier family 7member 1.Conclusion:Collectively,our findings provide the first in vivo evidence that ES robustly protects against CDDP-induced AKI by simultaneously targeting oxidative stress,inflammation,MAPK,and ER stress pathways,apoptosis,and ferroptosis.These results highlight ES as a potential candidate for preventing CDDP-induced nephrotoxicity.
基金financed by National Natural Science Foundation of China(Nos.81773642,52073139)Guangdong Provincial Clinical Research Center for Laboratory Medicine(No.2023B110008)the Provincial subsidies for the construction of high-level hospitals(No.K202201)。
文摘Liposomal drugs have significantly improved cancer treatment in recent years.However,the clinical application of conventional liposomes is limited by factors such as the complexity of the preparation process and the multitude of auxiliary components.By replacing phospholipids and cholesterol with vitamin E succinate(VES),this study addresses these shortcomings by developing a novel modified nanoprodrug,and the new formulation is used to deliver cisplatin.Concurrently,liposomes encapsulating cisplatin were prepared by conventional formulations for comparative experiments.Moreover,VES can inhibit the expression of mitochondrial uncoupling protein 2(UCP2),further enhancing mitochondrial damage in tumor cells within the tumor microenvironment(TME)and suppressing the tricarboxylic acid cycle,thereby reducing ATP production.Additionally,cisplatin damages DNA structure,affecting the binding of Nrf2 to the antioxidant response element(ARE),thereby inhibiting the signaling expression of heme oxygenase1(HO-1).The combined action of cisplatin and VES disrupts the redox balanceleading to a significant accumulation of reactive oxygen species(ROS).The nanoprodrug effectively alters the redox state of the TME and inhibits antioxidant defenses,thereby amplifying oxidative stress damage and enhancing the efficacy of cisplatin.Notably,compared to free cisplatin,the nanoprodrug demonstrates greater efficacy in both cell line-derived xenograft(CDX)and patient-derived tumor xenograft(PDX)liver cancer models.Overall,this study successfully develops a novel mitochondrial-targeted nanoprodrug by modifying the conventional liposome formulation.This provides a new strategy for amplifying oxidative stress in order to disrupt redox balance,and enhance cisplatin efficacy.
基金Supported by National Natural Science Foundation of China(81703001)Key R&D Project of Hebei Province(19277783D)+1 种基金Natural Science Foundation of Hebei Province(H2021406021)Chengde Medical University Discipline Construction Funds.
文摘[Objectives]To investigate whether Ailanthone(AIL)could reverse cisplatin resistance in non-small cell lung cancer(NSCLC)by modulating autophagy pathways in A549/DDP cells.[Methods]Cisplatin-resistant A549/DDP cells were treated with AIL(0.6μmol/L),cisplatin(50μg/mL),or their combination.Cell proliferation was assessed by MTT,EdU and colony formation assays;migration by Transwell and wound healing assays;autophagy markers(P62,LC3B,Beclin1,ATG5)by Western blot;LC3B puncta by immunofluorescence;with rescue experiments using rapamycin.[Results]The AIL-cisplatin combination synergistically inhibited proliferation and migration,while downregulating P-gp and MVP.AIL significantly increased P62 accumulation while decreasing LC3B-II,Beclin1 and ATG5.Rapamycin reversed these effects,restoring viability and resistance markers.[Conclusions]AIL reverses cisplatin resistance in NSCLC by inhibiting autophagy through P62/LC3B regulation,offering a promising therapeutic strategy for refractory NSCLC.
基金Liaoning Provincial Key Research and Development Program,Grant/Award Number:2024JH2/102500062China Health Promotion Foundation Spark Program,Grant/Award Number:XH-D001National Natural Science Foundation of China,Grant/Award Number:82104838。
文摘Cisplatin chemotherapy has been used as the main treatment for different types of cancer.However,cisplatin chemotherapy-induced peripheral neuropathic pain(CIPNP)seriously affects the treatment process and quality of life of patients.In addition,it impacts the underlying mechanism and prevention and treatment strategies,indicating that drug selection and efficacy evaluation need to be further investigated.Furthermore,an animal model that is more consistent with the pathological mechanism needs to be developed.In this study,we describe and discuss the methods of developing and detecting CIPNP models in rats and mice induced by cisplatin chemotherapy.The aim was to improve the modeling rate and develop animal models that are more consistent with the developmental pattern of the disease.In addition,the study provides ideal reference animal models for clinical research and drug discovery and development.
文摘Chemoresistance remains a major challenge in non-small cell lung cancer,especially for cisplatin(DDP)-based therapies,which are a mainstay of treatment.In their study,Dai et al investigate how inflammatory cytokines within the tumor microenvironment contribute to DDP resistance.By analyzing tumor samples from 20 non-small cell lung cancer patients and two resistant cell lines(A549/DDP and SK-MES-1/DDP),the authors show that increased levels of interleukin(IL)-6,IL-8,and tumor necrosis factor-αare linked to resistance.Logistic regression identifies IL-6 and IL-8 as key risk factors.Functional experiments using tocilizumab,an IL-6 receptor antagonist,demonstrate a reduction in DDP half maximum inhibitory concentration,higher apoptosis rates,and decreased migration and invasion in resistant cells.Although the study has certain limitations,such as the analysis of only five inflammatory cytokines in a small,non-stratified patient cohort;it demonstrates that targeting the IL-6 cytokine axis may help overcome DDP resistance.Overall,the study highlights the inflammatory component of the tumor microenvironment as a modifiable driver of chemoresistance and provide a rationale for integrating cytokine blockade into platinum-based chemotherapy regimens to enhance therapeutic response.
基金Supported by Shandong Provincial Natural Science Foundation,No.ZR2023MH329Project of Shandong Province Higher Educational Youth Innovation Science and Technology Program,No.2023KJ263and Natural Science Foundation of Gansu Province,China,No.22JR5RA953.
文摘BACKGROUND As a member of the chaperonin-containing tailless complex polypeptide 1(TCP1)complex,which plays a pivotal role in ensuring the accurate folding of numerous proteins,chaperonin-containing TCP1 subunit 6A(CCT6A)participates in various physiological and pathological processes.However,its effects on cell death and cancer therapy and the underlying mechanisms need further exploration in colorectal cancer(CRC)cells.AIM To explore the effects of CCT6A on cell death and cancer therapy and the underlying mechanisms in CRC.METHODS Cell proliferation was evaluated using the MTS assay,EdU staining,and colony growth assays.The expression of CCT6A was monitored by immunoblotting and quantitative PCR.CCT6A was knocked out by CRISPR-Cas9,and overexpressed by transfecting plasmids.Autophagy was examined by immunoblotting and the mCherry-GFP-LC3 assay.To monitor apoptosis and necroptosis,immunoblotting,co-immunoprecipitation,and flow cytometry were employed.RESULTS Cisplatin(DDP)exerted cytotoxic effects on CRC cells while simultaneously downregulating the expression of CCT6A.Depletion of CCT6A amplified the cytotoxic effects of DDP,whereas overexpression of CCT6A attenuated these adverse effects.CCT6A suppressed autophagy,apoptosis,and necroptosis under both basal and DDP-treated conditions.Autophagy inhibitors significantly enhanced the cytotoxic effects of DDP,whereas a necroptosis inhibitor partially reversed the cell viability loss induced by DDP.Furthermore,inhibiting autophagy enhanced both apoptosis and necroptosis induced by DDP.CONCLUSION CCT6A negatively modulates autophagy,apoptosis,and necroptosis,and CCT6A confers resistance to DDP therapy in CRC,suggesting its potential as a therapeutic target.
基金supported by the Scientific Research Program of Science and Technology Bureau of Huai’an City(Grant No.HAB202119).
文摘Background:Despite the identification of numerous therapeutic targets in lung cancer,achieving significant efficacy has been challenging.TNFRSF21 plays an important role in various cancers.We investigated the function of TNFRSF21 in lung adenocarcinoma(LUAD).Methods:The prognostic value of TNFRSF21 expression in lung cancer was evaluated by the GEPIA and Kaplan-Meier Plotter databases.Lung cancer cell viability was assessed by the CCK8 assay.TNFRSF21 expression patterns in lung cancer tissues and cells were examined using RT-PCR assay.Tumor sphere growth was evaluated through tumor sphere formation assays.MtROS contents in lung cancer cells were observed through MitoSOX fluorescent assays.Result:TNFRSF21 was up-regulated in LUAD patients.TNFRSF21 induction was particularly notable in LUAD,especially in cancerous cells(A549,H1299,H460,and SPC-A1),compared to BEAS-2B cells.Additionally,TNFRSF21 was increased in cisplatin(DDP)-resistant LUAD cells.Loss of TNFRSF21 significantly inhibited LUAD cell growth.It was observed that forced expression of TNFRSF21 contributed to tumor cell proliferation and DDP resistance.The production of ROS was found to participate in the inhibitory effects on lung cancer stem cells(CSCs),with decreased TNFRSF21 restraining ROS contents.Collectively,these findings reveal that the downregulation of TNFRSF21 promotes ROS contents to restrain the lung CSC-like characteristics via modulation of CD44 and CD133.Conclusions:In conclusion,TNFRSF21 may act as a novel target for lung cancer chemotherapy,particularly for eradicating lung CSCs.
文摘The published article titled“Overexpression of the Long Noncoding RNA FOXD2-AS1 Promotes Cisplatin Resistance in Esophageal Squamous Cell Carcinoma Through the miR-195/Akt/mTOR Axis”has been retracted from Oncology Research,Vol.28,No.1,2020,pp.65-73.
文摘The interaction of cisplatin and its analogues with phospholipid molecules of hu-man erythrocyte membranes was studied using IR and ￣31 P NMR methods. Dramatic changes were ob-served at 1300～953 cm￣-1 frequency region on the IR spectra .Based on the IR data analysis, it was speculated that the Pt(II) complexes interacted mainly with the polar head groups of phospholipids through electrostatic interaction and certain coordination patterns. The 1 2 h dynamic experiment showed that a recoverable process occurred in case of cis-DCDP and an unrecoverable one for other pt(II)analogues.A similar conclusion could be obtained from￣31 P NMR experimental results.The di-versity was discussed.
基金National Natural Science Foundation of China (Grant No.30472036).
文摘The antitumor activities of ethaselen （BBSKE） in combination with cisplatin （CDDP） in vitro have been investigated in human stomach cancer cell line BGC 823 and human lung cancer cell line PG-BE1. MTT method was used to assess the individual effects of ethaselen and cisplatin and their combined effects on cell proliferation of BGC 823 cells and PG-BE1 cells. Additionally, we used the classic median effect theory to calculate the combination index （CI） of ethaselen and cisplatin with different dose regimes in combination, and compared the effective dosages of cisplatin in individual treatment and combination treatment. When ethaselen and cisplatin were used in combination, a synergistic effect was observed. The most remarkable synergistic effect was observed when the dose ratio of cisplatin to ethaselen was 2：3 in BGC 823 cell line and 1：3 in PG-BE1 cell line. The dose of cisplatin could be decreased markedly in combination group to reach the same inhibitory effect, and this effect was gradually raised with the increase of the concentration of drugs.
基金supported in part by the National Natural Science Foundation of China(No.81372266)the National Science and Technology Major Project of the Ministry of Science and Technology of China(No.2011zx09101-001-03)
文摘It has been reported that Ethaselen shows inhibitory effects on thioredoxin reductase（TrxR） activity and human tumor cell growth. In order to find an efficient way to reverse cisplatin resistance, we investigated the reversal effects of Ethaselen on cisplatin resistance in K562/cisplatin（CDDP） cells that were established by pulse-inducing human erythrocyte leukemic cell line K562, which are fivefold more resistant to cisplatin compared to K562 cells. The morphology and growth showed that the adhesion of K562/CDDP further decreased while the cell volume increased. The proliferation of K562/CDDP is strengthened. The antitumor activities in vitro were assessed by MTT（3-（4,5-dimethylthiazol-2-yl）-2,5-diphenyltetrazolium bromide） assay and combination index（CI）, showing the significant synergic effects of cisplatin and Ethaselen. Focusing on apoptosis, a series of comparisons was made between K562 and K562/CDDP. Cisplatin induced higher reactive oxygen species（ROS） generation in K562 and subsequently induced the formation of mitochondrial permeability transition pores（PTPs）. In addition, cisplatin increased the ratio of Bax to Bcl-2 in K562, which can influence the mitochondrial membrane permeability. PTP formation and mitochondrial membrane permeabilization eventually resulted in the release of cytochrome c and activation of the Caspase pathway. However, these effects were not clearly seen in K562/CDDP, which may be the reason for the acquired CDDP resistance. However, Ethaselen can induce a high level of ROS in K562/CDDP by TrxR activity inhibition and increased ratio of Bax to Bcl-2 in K562/CDDP by nuclear factor κB（NF-κB） suppression, which subsequently induces the release of cytochrome c in K562/CDDP. This response is partly responsible for the reversal of the cisplatin resistance in K562/CDDP cells.
文摘The interaction between cisplatin and erythrocyte membrane proteins was studied based on the quenching effect of cisplatin on the intrinsic fluorescence of proteins.A concentration-dependent quenching effect was observed.The presence of chloride and sulphate weakens the effect significantly.A pH-dependence was also noted with a stronger effect in acidic solution. The nature of the interaction is considered to be platinum-thiol group binding according to the effect of cisplatin on the fluorescence of FMA labeled membrane. The mechanism of the cisplatin-protein interactions was discussed based on the effect of coexisting anion
文摘Acute Kidney Injury (AKI) is a condition that causes nephrotoxicity in kidney tissues due to cisplatin-induced cancer treatments. Hence, it is proposed in this review that AVE0991 (a MAS-receptor Angiotensin II (1-7) agonist) may reduce cisplatin-induced acute kidney injury by promoting nitric oxide production.
