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
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
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
Cisplatin resistance is the main cause for the failure of cancer therapy.To solve the problem,we proposed to develop a novel human serum albumin(HSA)nanoplatform to integrate chemotherapy,photothermal therapy(PTT)and ...Cisplatin resistance is the main cause for the failure of cancer therapy.To solve the problem,we proposed to develop a novel human serum albumin(HSA)nanoplatform to integrate chemotherapy,photothermal therapy(PTT)and immunotherapy.To this end,we obtained a platinum compound(C5)with significant cytotoxicity in the cisplatin-resistant SKOV-3 cells(SKOV-3/DDP),and then innovatively constructed photosensitizer(indocyanine green(ICG))-encapsulated HSAC5 complex nanoparticles(ICG@HSA-C5 NPs).The ICG@HSA-C5 NPs exhibited excellent photothermal performances in vitro and in vivo.Importantly,the in vivo results revealed that HSA enhanced the antitumor effect of C5 and that the combination of chemotherapy and PTT could significantly inhibit cisplatin-resistant tumor growth and improved the targeting abilities of C5 and ICG,and reduced their side effects.We also confirmed that ICG@HSA-C5 NPs killed the SKOV-3/DDP cells via gasdermin E(GSDME)-mediated pyroptosis and pyroptosis-induced immune responses,thereby synergistically leading to the death of the SKOV-3/DDP cells.展开更多
Objectives:Deletion of Fscn2 gene in mice has been linked to progressive hearing loss and degeneration of cochlear cells.Cisplatin,an antitumor drug,can cause various side effects,including ototoxicity.The aim of this...Objectives:Deletion of Fscn2 gene in mice has been linked to progressive hearing loss and degeneration of cochlear cells.Cisplatin,an antitumor drug,can cause various side effects,including ototoxicity.The aim of this study was to investigate the effects of Fscn2 on cisplatin-induced hearing impairment in mice and to explore the possible mechanism.Methods:Two-week-old Fscn2^(+/+)mice and Fscn2^(−/−)mice were treated with two doses of cisplatin,with a 3-day recovery period in between.ABR(auditory evoked brain stem response)thresholds were measured and cochlear pathology was observed at 3 weeks of age.Results:Both Fscn2^(+/+)and Fscn2^(−/−)mice showed hearing loss under the effect of cisplatin,but the impairment was more severe in Fscn2^(−/−)mice.Further experiments showed that the percentages of outer hair cell(OHC)and spiral ganglion neuron(SGN)loss were significantly higher in cisplatin-treated Fscn2^(−/−)mice compared to Fscn2^(+/+)mice.Additionally,knockdown of Fscn2 in HEI-OC1 cells worsened cisplatin-induced cell apoptosis.Conclusion:FSCN2 mediates reduction of CDDP induced ototoxicity by inhibiting cell apoptosis.展开更多
Combining phototherapy and chemotherapy has been considered a promising modality for cancer therapy due to their synergistic effect.Herein,we developed three D-π-A-structured boron dipyrromethenes(BODIPYs)(named as B...Combining phototherapy and chemotherapy has been considered a promising modality for cancer therapy due to their synergistic effect.Herein,we developed three D-π-A-structured boron dipyrromethenes(BODIPYs)(named as B-B,B-C,and B-C-Pt).Due to their enlargedπ-conjugated structure and high intramolecular charge transfer effect,the synthesized BODIPYs had photothermal conversion capability,and their absorption and fluorescence spectra were red-shifted.The cisplatin-appended BODIPY(B-C-Pt)exhibited good singlet oxygen(^1O_(2))generation ability and near infrared(NIR)absorption and fluorescence(λ_(Abs)=748 nm,λ_(Em)=947 nm).After being encapsulated by distearoyl phosphoethanolamine polyethyleneglycol 2000(DSPE-PEG-2000),which could inhibit the H-aggregation of B-C-Pt,the absorption and fluorescence of the obtained B-C-Pt nanoparticles(NPs)were red-shifted to 762 and 985 nm,respectively.The^1O_(2)quantum yield and photothermal conversion efficiency of the B-C-Pt NPs were 4.0%and 40.6%,respectively.Moreover,B-C-Pt NPs had chemotherapeutic efficacy due to the presence of cisplatin.In vitro and in vivo studies further demonstrated that B-C-Pt NPs had synergistic therapeutic efficacy.Together,B-C-Pt NPs could be employed in NIRⅡfluorescent and photoacoustic imaging-guided synergistic phototherapy and chemotherapy for cancer treatment.展开更多
The platinum-based chemotherapy is one of the most frequently used treatment protocols for lung adenocarcinoma(LUAD),and chemoresistance,however,usually results in treatment failure and limits its application in the c...The platinum-based chemotherapy is one of the most frequently used treatment protocols for lung adenocarcinoma(LUAD),and chemoresistance,however,usually results in treatment failure and limits its application in the clinic.It has been shown that microRNAs(miRNAs)play a significant role in tumor chemoresistance.In this study,miR-125b was identified as a specific cisplatin(DDP)-resistant gene in LUAD,as indicated by the bioinformatics analysis and the real-time quantitative PCR assay.The decreased serum level of miR-125b in LUAD patients was correlated with the poor treatment response rate and short survival time.MiR-125b decreased the A549/DDP proliferation,and the multiple drug resistance-and autophagy-related protein expression levels,which were all reversed by the inhibition of miR-125b.In addition,xenografts of human tumors in nude mice were suppressed by miR-125b,demonstrating that through autophagy regulation,miR-125b could reverse the DDP resistance in LUAD cells,both in vitro and in vivo.Further mechanistic studies indicated that miR-125b directly repressed the expression levels of RORA and its downstream BNIP3L,which in turn inhibited autophagy and reversed chemoresistance.Based on these findings,miR-125b in combination with DDP might be an effective treatment option to overcome DDP resistance in LUAD.展开更多
The impact of different iron metabolism processes(DIMP)on ovarian cancer remains unclear.In this study,we employed various gene chips and databases to investigate the role of DIMP in the initiation and development of ...The impact of different iron metabolism processes(DIMP)on ovarian cancer remains unclear.In this study,we employed various gene chips and databases to investigate the role of DIMP in the initiation and development of ovarian cancer.cBioPortal was used to determine mutations in DIMP-associated genes in ovarian cancer.Kaplan-Meier plotter was used to examine the influence of DIMP on the prognosis of ovarian cancer.By analyzing 1669 serous ovarian cancer cases,we identified a range of mutations in iron metabolism genes,notably in those coding for the transferrin receptor(19%),melanotransferrin(19%),and ceruloplasmin(10%)in the iron import process,and glucose-6-phosphate isomerase(9%),hepcidin antimicrobial peptide(9%),metal regulatory transcription factor 1(8%),and bone morphogenetic protein 6(8%)in the iron regulation process.Compared to the unaltered group,the group with gene alterations exhibited a higher tumor mutation burden count(43 vs.54)and more advanced histologic grade(78.19%vs.87.90%).Compared to the normal ovarian counterparts,a reduction in expression was observed in 9 out of the 14 genes involved in iron utilization and 4 out of the 5 genes involved in iron export in ovarian cancer;in contrast,an increase in expression was observed in 2 out of the 3 genes involved in iron storage in ovarian cancer.Furthermore,in cisplatin-resistant cells compared to cisplatin-sensitive ones,the expression of all genes in iron storage and 13 out of 14 genes in iron import was decreased,while that of 8 out of the 10 genes in iron utilization was increased.In addition,survival curve analysis indicated that a higher expression in the majority of genes in the iron import process(12/21),or a reduced expression in most genes in the iron export process(4/5)correlated with poor progression-free survival.Additionally,TGF-βcould regulate the expression of most iron metabolism-associated genes;particularly,expression of genes involved in the iron storage process(2/2)was inhibited after TGF-β1 or TGF-β2 treatment.In conclusion,DIMP plays multifaceted roles in the initiation,chemo-resistance,and prognosis of ovarian cancer.Therapeutically targeting DIMP may pave the way for more tailored treatment approaches for ovarian cancer.展开更多
Growing evidence suggests an association between epithelial-mesenchymal transition(EMT),a hallmark of tumor malignancy,and chemoresistance to a number of anti-cancer drugs.However,the mechanism of EMT induction in the...Growing evidence suggests an association between epithelial-mesenchymal transition(EMT),a hallmark of tumor malignancy,and chemoresistance to a number of anti-cancer drugs.However,the mechanism of EMT induction in the process of acquiring anti-cancer drug resistance remains unclear.To address this issue,we obtained a number of cisplatin-resistant clones from LoVo cells and found that almost all of them lost cell-cell contacts.In these clones,the epithelial marker E-cadherin was downregulated,whereas the mesenchymal marker N-cadherin was upregulated.Moreover,the expression of EMT-related transcription factors,including Slug,was elevated.On the other hand,the upregulation of other mesenchymal marker Vimentin was weak,suggesting that the mesenchymal-like phenotypic changes occurred in these cisplatin-resistant clones.These mesenchymal-like features of cisplatin-resistant clones were partially reversed to parental epithelial-like features by treatment with transforming growth factor-β(TGF-β)receptor kinase inhibitors,indicating that TGF-βsignaling is involved in cisplatin-induced the mesenchymallike phenotypic changes.Moreover,cisplatin was observed to enhance the secretion of TGF-βinto the culture media without influencing TGF-βgene transcription.These results suggest that cisplatin may induce the mesenchymal-like phenotypic changes by enhancing TGF-βsecretion,ultimately resulting in drug resistance.展开更多
Background:Head and neck squamous cell carcinoma(HNSCC)is a prevalent form of cancer globally,with chemoresistance posing a major challenge in treatment outcomes.The efficacy of the commonly used chemotherapeutic agent...Background:Head and neck squamous cell carcinoma(HNSCC)is a prevalent form of cancer globally,with chemoresistance posing a major challenge in treatment outcomes.The efficacy of the commonly used chemotherapeutic agent,cisplatin,is diminished in patients with poor prognoses.Methods:Various bioinformatics databases were utilized to examine Carboxylesterase 1(CES1)gene expression,clinicopathologic features,patient survival analysis,and gene function.An organoid model of HNSCC was established,along with the induction of drug-resistant HNSCC in the organoid model.CES1 expression was assessed using qRT-PCR and Western Blot,and differential markers were identified through transcriptome sequencing.Knockdown and overexpression models of CES1 were created in SCC-9 and patient-derived organoid(PDO)cells using shRNA and lentivirus to investigate the tumor biology and cisplatin resistance associated with CES1.Results:Research in bioinformatics has uncovered a strong correlation between the expression level of CES1 and the prognosis of HNSCC.The data suggests a significant link between CES1 expression and tobacco smoking.RNA-sequencing revealed a notable increase in CES1 expression in HNSCC-PDOcis-R cells compared to the parental PDO cells.Subsequently,we performed in vitro studies by HNSCC-PDO and SCC-9 and found that CES1-overexpressing cells exhibited reduced sensitivity to cisplatin and stronger tumor malignant biological behavior compared with CES1-knockdown cells.Conclusion:The observed association between CES1 expression and tobacco smoking implies a potential influence of smoking on the efficacy of cisplatin-based chemotherapy in HNSCC through the regulation of CES1 expression.展开更多
Celecoxib,a cyclooxygenase-2 inhibitor,can enhance the efficacy of chemotherapy;however,its effect seems inconsistent.In this study,we investigated whether celecoxib would increase the antiproliferative effects of cis...Celecoxib,a cyclooxygenase-2 inhibitor,can enhance the efficacy of chemotherapy;however,its effect seems inconsistent.In this study,we investigated whether celecoxib would increase the antiproliferative effects of cisplatin in human lung cancer cells.Our data demonstrated the synergistic effects of celecoxib with cisplatin in wild-type p53 cells and their antagonistic effects inmutated or deleted p53 cells.Combination indices of 0.82 to 0.93 reflected a synergistic effect between celecoxib and cisplatin in lung cancer cells with wild-type p53.Combination indices of 1.63 to 3.00 reflected antagonism between celecoxib and cisplatin in lung cancer cells with mutated or deleted p53.Compared with that in cells with mutated or deleted p53,apoptosis significantly increased with the addition of celecoxib and cisplatin in wild-type p53 cells(P<0.05).Moreover,the results in vivo were similar to those in vitro:celecoxib combinedwith cisplatin slowed tumor growth in wild-type p53 groups and not in mutated or deleted p53 groups.In addition,celecoxib promoted p53 translocation into the nucleus and upregulated active p53 expression in wild-type p53 cells.Celecoxib combined with cisplatin upregulated PUMA(PUMA is a downstream gene of p53)after active p53 increased in wild-type p53 cells.In summary,the combination of celecoxib and cisplatin demonstrates clear synergistic effects in wild-type p53 cells and antagonistic effects inmutated or deleted p53 cells.The synergistic effect was achieved by apoptosis,induced by upregulating PUMA.Our results will provide a new treatment strategy for patients carrying wild-type p53,insensitive to cisplatin.展开更多
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.
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.
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.
基金financially supported by the Natural Science Foundation of China(No.22077021)the Natural Science Foundation of Guangxi(No.2022GXNSFGA035003)。
文摘Cisplatin resistance is the main cause for the failure of cancer therapy.To solve the problem,we proposed to develop a novel human serum albumin(HSA)nanoplatform to integrate chemotherapy,photothermal therapy(PTT)and immunotherapy.To this end,we obtained a platinum compound(C5)with significant cytotoxicity in the cisplatin-resistant SKOV-3 cells(SKOV-3/DDP),and then innovatively constructed photosensitizer(indocyanine green(ICG))-encapsulated HSAC5 complex nanoparticles(ICG@HSA-C5 NPs).The ICG@HSA-C5 NPs exhibited excellent photothermal performances in vitro and in vivo.Importantly,the in vivo results revealed that HSA enhanced the antitumor effect of C5 and that the combination of chemotherapy and PTT could significantly inhibit cisplatin-resistant tumor growth and improved the targeting abilities of C5 and ICG,and reduced their side effects.We also confirmed that ICG@HSA-C5 NPs killed the SKOV-3/DDP cells via gasdermin E(GSDME)-mediated pyroptosis and pyroptosis-induced immune responses,thereby synergistically leading to the death of the SKOV-3/DDP cells.
基金supported by the National Natural Science Foundation of China(No.81771020,81570927 and 81271092)Grant for Scientific and Technological Development Plan for Medical and Health in Shandong Province(2019WS341).
文摘Objectives:Deletion of Fscn2 gene in mice has been linked to progressive hearing loss and degeneration of cochlear cells.Cisplatin,an antitumor drug,can cause various side effects,including ototoxicity.The aim of this study was to investigate the effects of Fscn2 on cisplatin-induced hearing impairment in mice and to explore the possible mechanism.Methods:Two-week-old Fscn2^(+/+)mice and Fscn2^(−/−)mice were treated with two doses of cisplatin,with a 3-day recovery period in between.ABR(auditory evoked brain stem response)thresholds were measured and cochlear pathology was observed at 3 weeks of age.Results:Both Fscn2^(+/+)and Fscn2^(−/−)mice showed hearing loss under the effect of cisplatin,but the impairment was more severe in Fscn2^(−/−)mice.Further experiments showed that the percentages of outer hair cell(OHC)and spiral ganglion neuron(SGN)loss were significantly higher in cisplatin-treated Fscn2^(−/−)mice compared to Fscn2^(+/+)mice.Additionally,knockdown of Fscn2 in HEI-OC1 cells worsened cisplatin-induced cell apoptosis.Conclusion:FSCN2 mediates reduction of CDDP induced ototoxicity by inhibiting cell apoptosis.
基金supported by National Natural Science Foundation of China(No.62175262)the Science and Technology Innovation Program of Hunan Province(No.2022RC1201)the Fundamental Research Funds for the Central Universities of Central South University(No.2019zzts849)。
文摘Combining phototherapy and chemotherapy has been considered a promising modality for cancer therapy due to their synergistic effect.Herein,we developed three D-π-A-structured boron dipyrromethenes(BODIPYs)(named as B-B,B-C,and B-C-Pt).Due to their enlargedπ-conjugated structure and high intramolecular charge transfer effect,the synthesized BODIPYs had photothermal conversion capability,and their absorption and fluorescence spectra were red-shifted.The cisplatin-appended BODIPY(B-C-Pt)exhibited good singlet oxygen(^1O_(2))generation ability and near infrared(NIR)absorption and fluorescence(λ_(Abs)=748 nm,λ_(Em)=947 nm).After being encapsulated by distearoyl phosphoethanolamine polyethyleneglycol 2000(DSPE-PEG-2000),which could inhibit the H-aggregation of B-C-Pt,the absorption and fluorescence of the obtained B-C-Pt nanoparticles(NPs)were red-shifted to 762 and 985 nm,respectively.The^1O_(2)quantum yield and photothermal conversion efficiency of the B-C-Pt NPs were 4.0%and 40.6%,respectively.Moreover,B-C-Pt NPs had chemotherapeutic efficacy due to the presence of cisplatin.In vitro and in vivo studies further demonstrated that B-C-Pt NPs had synergistic therapeutic efficacy.Together,B-C-Pt NPs could be employed in NIRⅡfluorescent and photoacoustic imaging-guided synergistic phototherapy and chemotherapy for cancer treatment.
基金supported by the National Natural Science Foundation of China(No.81703001)the Natural Science Foundation of Hebei Province(No.H2021406021),Hebei Province Medical Science Research Project(Nos.20210247,20221335)Hebei Province Government-Funded Clinical Medical Outstanding Talents Project,Chengde Medical University Scientific Research Major Projects(No.KY2020005).
文摘The platinum-based chemotherapy is one of the most frequently used treatment protocols for lung adenocarcinoma(LUAD),and chemoresistance,however,usually results in treatment failure and limits its application in the clinic.It has been shown that microRNAs(miRNAs)play a significant role in tumor chemoresistance.In this study,miR-125b was identified as a specific cisplatin(DDP)-resistant gene in LUAD,as indicated by the bioinformatics analysis and the real-time quantitative PCR assay.The decreased serum level of miR-125b in LUAD patients was correlated with the poor treatment response rate and short survival time.MiR-125b decreased the A549/DDP proliferation,and the multiple drug resistance-and autophagy-related protein expression levels,which were all reversed by the inhibition of miR-125b.In addition,xenografts of human tumors in nude mice were suppressed by miR-125b,demonstrating that through autophagy regulation,miR-125b could reverse the DDP resistance in LUAD cells,both in vitro and in vivo.Further mechanistic studies indicated that miR-125b directly repressed the expression levels of RORA and its downstream BNIP3L,which in turn inhibited autophagy and reversed chemoresistance.Based on these findings,miR-125b in combination with DDP might be an effective treatment option to overcome DDP resistance in LUAD.
基金supported by Academic Leader Training Program of Pudong New Area Health System in Shanghai(Grant No.PWRd2021-13).
文摘The impact of different iron metabolism processes(DIMP)on ovarian cancer remains unclear.In this study,we employed various gene chips and databases to investigate the role of DIMP in the initiation and development of ovarian cancer.cBioPortal was used to determine mutations in DIMP-associated genes in ovarian cancer.Kaplan-Meier plotter was used to examine the influence of DIMP on the prognosis of ovarian cancer.By analyzing 1669 serous ovarian cancer cases,we identified a range of mutations in iron metabolism genes,notably in those coding for the transferrin receptor(19%),melanotransferrin(19%),and ceruloplasmin(10%)in the iron import process,and glucose-6-phosphate isomerase(9%),hepcidin antimicrobial peptide(9%),metal regulatory transcription factor 1(8%),and bone morphogenetic protein 6(8%)in the iron regulation process.Compared to the unaltered group,the group with gene alterations exhibited a higher tumor mutation burden count(43 vs.54)and more advanced histologic grade(78.19%vs.87.90%).Compared to the normal ovarian counterparts,a reduction in expression was observed in 9 out of the 14 genes involved in iron utilization and 4 out of the 5 genes involved in iron export in ovarian cancer;in contrast,an increase in expression was observed in 2 out of the 3 genes involved in iron storage in ovarian cancer.Furthermore,in cisplatin-resistant cells compared to cisplatin-sensitive ones,the expression of all genes in iron storage and 13 out of 14 genes in iron import was decreased,while that of 8 out of the 10 genes in iron utilization was increased.In addition,survival curve analysis indicated that a higher expression in the majority of genes in the iron import process(12/21),or a reduced expression in most genes in the iron export process(4/5)correlated with poor progression-free survival.Additionally,TGF-βcould regulate the expression of most iron metabolism-associated genes;particularly,expression of genes involved in the iron storage process(2/2)was inhibited after TGF-β1 or TGF-β2 treatment.In conclusion,DIMP plays multifaceted roles in the initiation,chemo-resistance,and prognosis of ovarian cancer.Therapeutically targeting DIMP may pave the way for more tailored treatment approaches for ovarian cancer.
基金the Japan Society for the Promotion of Science(JSPS),KAKENHI,Grant Number 26350974.
文摘Growing evidence suggests an association between epithelial-mesenchymal transition(EMT),a hallmark of tumor malignancy,and chemoresistance to a number of anti-cancer drugs.However,the mechanism of EMT induction in the process of acquiring anti-cancer drug resistance remains unclear.To address this issue,we obtained a number of cisplatin-resistant clones from LoVo cells and found that almost all of them lost cell-cell contacts.In these clones,the epithelial marker E-cadherin was downregulated,whereas the mesenchymal marker N-cadherin was upregulated.Moreover,the expression of EMT-related transcription factors,including Slug,was elevated.On the other hand,the upregulation of other mesenchymal marker Vimentin was weak,suggesting that the mesenchymal-like phenotypic changes occurred in these cisplatin-resistant clones.These mesenchymal-like features of cisplatin-resistant clones were partially reversed to parental epithelial-like features by treatment with transforming growth factor-β(TGF-β)receptor kinase inhibitors,indicating that TGF-βsignaling is involved in cisplatin-induced the mesenchymallike phenotypic changes.Moreover,cisplatin was observed to enhance the secretion of TGF-βinto the culture media without influencing TGF-βgene transcription.These results suggest that cisplatin may induce the mesenchymal-like phenotypic changes by enhancing TGF-βsecretion,ultimately resulting in drug resistance.
基金supported by the National Natural Science Foundation of China(No.82160386)the Guangxi Natural Science Foundation of China(No.2024GXNSFDA010032,2023GXNSFAA026189).
文摘Background:Head and neck squamous cell carcinoma(HNSCC)is a prevalent form of cancer globally,with chemoresistance posing a major challenge in treatment outcomes.The efficacy of the commonly used chemotherapeutic agent,cisplatin,is diminished in patients with poor prognoses.Methods:Various bioinformatics databases were utilized to examine Carboxylesterase 1(CES1)gene expression,clinicopathologic features,patient survival analysis,and gene function.An organoid model of HNSCC was established,along with the induction of drug-resistant HNSCC in the organoid model.CES1 expression was assessed using qRT-PCR and Western Blot,and differential markers were identified through transcriptome sequencing.Knockdown and overexpression models of CES1 were created in SCC-9 and patient-derived organoid(PDO)cells using shRNA and lentivirus to investigate the tumor biology and cisplatin resistance associated with CES1.Results:Research in bioinformatics has uncovered a strong correlation between the expression level of CES1 and the prognosis of HNSCC.The data suggests a significant link between CES1 expression and tobacco smoking.RNA-sequencing revealed a notable increase in CES1 expression in HNSCC-PDOcis-R cells compared to the parental PDO cells.Subsequently,we performed in vitro studies by HNSCC-PDO and SCC-9 and found that CES1-overexpressing cells exhibited reduced sensitivity to cisplatin and stronger tumor malignant biological behavior compared with CES1-knockdown cells.Conclusion:The observed association between CES1 expression and tobacco smoking implies a potential influence of smoking on the efficacy of cisplatin-based chemotherapy in HNSCC through the regulation of CES1 expression.
基金the Beijing Municipal Science and Technology Commission(grant Z211100002921013)the Tongzhou District Science and Technology Committee Project to Tongzhou(grant KJ2020CX010).
文摘Celecoxib,a cyclooxygenase-2 inhibitor,can enhance the efficacy of chemotherapy;however,its effect seems inconsistent.In this study,we investigated whether celecoxib would increase the antiproliferative effects of cisplatin in human lung cancer cells.Our data demonstrated the synergistic effects of celecoxib with cisplatin in wild-type p53 cells and their antagonistic effects inmutated or deleted p53 cells.Combination indices of 0.82 to 0.93 reflected a synergistic effect between celecoxib and cisplatin in lung cancer cells with wild-type p53.Combination indices of 1.63 to 3.00 reflected antagonism between celecoxib and cisplatin in lung cancer cells with mutated or deleted p53.Compared with that in cells with mutated or deleted p53,apoptosis significantly increased with the addition of celecoxib and cisplatin in wild-type p53 cells(P<0.05).Moreover,the results in vivo were similar to those in vitro:celecoxib combinedwith cisplatin slowed tumor growth in wild-type p53 groups and not in mutated or deleted p53 groups.In addition,celecoxib promoted p53 translocation into the nucleus and upregulated active p53 expression in wild-type p53 cells.Celecoxib combined with cisplatin upregulated PUMA(PUMA is a downstream gene of p53)after active p53 increased in wild-type p53 cells.In summary,the combination of celecoxib and cisplatin demonstrates clear synergistic effects in wild-type p53 cells and antagonistic effects inmutated or deleted p53 cells.The synergistic effect was achieved by apoptosis,induced by upregulating PUMA.Our results will provide a new treatment strategy for patients carrying wild-type p53,insensitive to cisplatin.
