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
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
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
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
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
De spite cisplatin has been widely used in the treatment of various cancers,the noteworthy nephrotoxicity greatly constrained its clinical value.For this reason,finding novel targeted therapies to attenuate the nephro...De spite cisplatin has been widely used in the treatment of various cancers,the noteworthy nephrotoxicity greatly constrained its clinical value.For this reason,finding novel targeted therapies to attenuate the nephrotoxicity of cisplatin should be pretty significant.Our previous study found that histone deacetylase sirtuin 6(SIRT6)could be an ideal target for the treatment of cisplatin-induced acute kidney injury.In this study,we explored the protective effects of ellagic acid,a natural polyphenol compound that activates SIRT6,on cisplatin-induced nephrotoxicity.Pre-treatment of ellagic acid attenuated cytotoxicity of cisplatin in primary renal cells and TCMK-1 cells.Moreover,ellagic acid ameliorated renal dysfunction,apoptosis and fibrosis induced by cisplatin in mice.Furthermore,ellagic acid reduced nephrotoxicity-associated inflammatory factor interleukin(IL)-1βand IL-6 expression both in vitro and in vivo.Mechanistically,ellagic acid reversed cisplatin-reduced SIRT6 expression and diminished cisplatin-induced tumor necrosis factor(TNF)-αexpression.And SIRT6 knockdown abrogated the protective effects of ellagic acid on cisplatin-induced cell apoptosis,indicating the renal-protective effects of ellagic acid are mainly dependent on ellagic acid-mediated SIRT6 activation.Our results provide preclinical rationale for using ellagic acid as a feasible and promising agent to ameliorate cisplatin-induced acute kidney injury,and support ellagic acid as a potential adjunctive therapy for future cancer treatment.展开更多
Anti-cancer therapy often causes premature ovarian insufficiency and infertility as the ovarian follicle reserve is extremely sensitive to chemotherapy drugs,such as cisplatin.Various fertility preservation methods ha...Anti-cancer therapy often causes premature ovarian insufficiency and infertility as the ovarian follicle reserve is extremely sensitive to chemotherapy drugs,such as cisplatin.Various fertility preservation methods have been explored for women,especially prepubertal girls undergoing radiotherapy and chemotherapy due to cancer.In recent years,mesenchymal stem cell-derived exosomes(MSC-exos)have been reported to play an important role in tissue repair and the treatment of various diseases.In the current study,we observed that human umbilical cord-derived MSC-exos(hucMSC-exos)after short-term culture improved follicular survival and development while receiving cisplatin treatment.Moreover,intravenous injection of hucMSC-exos improved ovarian function and ameliorated inflammatory environment within the ovary.The underlying mechanism of hucMSC-exos on fertility preservation was associated with the down-regulation of p53-related apoptosis and their anti-inflammatory function.Based on these findings,we propose that hucMSC-exos may be a potential approach to improve fertility in women diagnosed with cancer.展开更多
Hepatoblastoma is the most frequent liver malignancy in children.HepG2 has been discovered as a hepatoblastoma-derived cell line and tends to form clumps in culture.Intriguingly,we observed that the addition of calciu...Hepatoblastoma is the most frequent liver malignancy in children.HepG2 has been discovered as a hepatoblastoma-derived cell line and tends to form clumps in culture.Intriguingly,we observed that the addition of calcium ions reduced cell clumping and disassociated HepG2 cells.The calcium signal is in connection with a series of processes critical in the tumorigenesis.Here,we demonstrated that extracellular calcium ions induced morphological changes and enhanced the epithelial-mesenchymal transition in HepG2 cells.Mechanistically,calcium ions promoted HepG2 proliferation and migration by up-regulating the phosphorylation levels of focal adhesion kinase(FAK),protein kinase B,and p38 mitogen-activated protein kinase.The inhibitor of FAK or Ca2+/calmodulin-dependent kinaseⅡ(CaMKⅡ)reversed the Ca2+-induced effects on HepG2 cells,including cell proliferation and migration,epithelial-mesenchymal transition protein expression levels,and phosphorylation levels of FAK and protein kinase B.Moreover,calcium ions decreased HepG2 cells'sensitivity to cisplatin.Furthermore,we found that the expression levels of FAK and CaMKⅡwere increased in hepatoblastoma.The group with high expression levels of FAK and CaMKⅡexhibited significantly lower ImmunoScore as well as CD8+T and NK cells.The expression of CaMKⅡwas positively correlated with that of PDCD1 and LAG3.Correspondingly,the expression of FAK was negatively correlated with that of TNFSF9,TNFRSF4,and TNFRSF18.Collectively,extracellular calcium accelerates HepG2 cell proliferation and migration via FAK and CaMKⅡand enhances cisplatin resistance.FAK and CaMKⅡshape immune cell infiltration and responses in tumor microenvironments,thereby serving as potential targets for hepatoblastoma.展开更多
Objective Cisplatin is the first-line treatment for breast cancer,but it faces challenges of drug resistance.This study investigated new molecular mechanisms underlying cisplatin resistance in breast cancer.Methods We...Objective Cisplatin is the first-line treatment for breast cancer,but it faces challenges of drug resistance.This study investigated new molecular mechanisms underlying cisplatin resistance in breast cancer.Methods We analyzed sequencing data from the TCGA database to identify potential associations between transmembrane emp24 protein transport domain containing 2(TMED2)and breast cancer.Western blotting,real-time PCR,CCK-8,and TUNEL assays were used to measure the effects and molecular mechanism of TMED2 on cisplatin resistance in MCF-7 and MDA-MB-231 cell lines.Results TMED2 was overexpressed in breast cancer and associated with poor prognosis.TMED2 increased cisplatin resistance in breast cancer cells in vitro via promoting ubiquitination of Kelch-like ECH-associated protein 1(KEAP1),relieving inhibition of KEAP1 on nuclear factor erythroid 2-related factor 2(Nrf2),and increasing expression of downstream drug resistance related genes,such as heme oxygenase 1(HO-1)and NAD(P)H quinone oxidoreductase 1(NQO1).Conclusion We identified a new molecular mechanism by which TMED2 affects cisplatin resistance in breast cancer.Our results provide theoretical guidance for future clinical applications.展开更多
The low survival rate of Kidney renal clear cell carcinoma(KIRC)patients is largely attributed to cisplatin resistance.Rather than focusing solely on individual proteins,exploring protein-protein interactions could of...The low survival rate of Kidney renal clear cell carcinoma(KIRC)patients is largely attributed to cisplatin resistance.Rather than focusing solely on individual proteins,exploring protein-protein interactions could offer greater insight into drug resistance.To this end,a series of in silico and in vitro experiments were conducted to identify hub genes in the intricate network of cisplatin resistance-related genes in KIRC chemotherapy.The genes involved in cisplatin resistance across KIRC were retrieved from the National Center for Biotechnology Information(NCBI)database using search terms as“Kidney renal clear cell carcinoma”and“Cisplatin resistance”.The genes retrieved were analyzed for hub gene identification using the STRING database and Cytoscape tool.Expression and promoter methylation profiling of the hub genes was done using UALCAN,GEPIA,OncoDB,and HPA databases.Mutational,survival,functional enrichment,immune cell infiltration,and drug prediction analyses of the hub genes were performed using the cBioPortal,GEPIA,GSEA,TIMER,and DrugBank databases.Lastly,expression and methylation levels of the hub genes were validated on two cisplatin-resistant RCC cell lines(786-O and A-498)and a normal renal tubular epithelial cell line(HK-2)using two high throughput techniques,including targeted bisulfite sequencing(bisulfite-seq)and RT-qPCR.A total of 124 genes were identified as being associated with cisplatin resistance in KIRC.Out of these genes,MCL1,IGF1R,CCND1,and PTEN were identified as hub genes and were found to have significant(p<0.05)variations in their mRNA and protein expressions and effects on the overall survival(OS)of the KIRC patients.Moreover,an aberrant promoter methylation pattern was found to be associated with the dysregulation of the hub genes.In addition to this,hub genes were also linked with different cisplatin resistance-causing pathways.Thus,hub genes can be targeted with Alvocidib,Estradiol,Tretinoin,Capsaicin,Dronabinol,Metribolone,Calcitriol,Acetaminophen,Acitretin,Cyclosporine,Azacitidine,Genistein,and Resveratrol drugs.As the pathogenesis of KIRC is complex,targeting hub genes and associated pathways involved in cisplatin resistance could bring a milestone change in the drug discovery and management of drug resistance,which might uplift overall survival among KIRC patients.展开更多
This study aimed to evaluate the therapeutic potential of inhibiting protein arginine methyltransferase 5(PRMT5)in cisplatin-induced hearing loss.The effects of PRMT5 inhibition on cisplatin-induced auditory injury we...This study aimed to evaluate the therapeutic potential of inhibiting protein arginine methyltransferase 5(PRMT5)in cisplatin-induced hearing loss.The effects of PRMT5 inhibition on cisplatin-induced auditory injury were determined using immunohistochemistry,apoptosis assays,and auditory brainstem response.The mechanism of PRMT5 inhibition on hair cell survival was assessed using RNA-seq and Cleavage Under Targets and Tagment-quantitative polymerase chain reaction(CUT&Tag-qPCR)analyses in the HEI-OC1 cell line.Pharmacological inhibition of PRMT5 significantly alleviated cisplatin-induced damage to hair cells and spiral ganglion neurons in the cochlea and decreased apoptosis by protecting mitochondrial function and preventing the accumulation of reactive oxygen species.CUT&Tag-qPCR analysis demonstrated that inhibition of PRMT5 in HEI-OC1 cells reduced the accumulation of H4R3me2s/H3R8me2s marks at the promoter region of the Pik3ca gene,thus activating the expression of Pik3ca.These findings suggest that PRMT5 inhibitors have strong potential as agents against cisplatininduced ototoxicity and can lay the foundation for further research on treatment strategies of hearing loss.展开更多
The original version of this article was revised due to production error by the vendor.The author“Hua-min DING”is one of the co-authors,and the name should be labeled correctly as appears on PDF.The affiliation of“...The original version of this article was revised due to production error by the vendor.The author“Hua-min DING”is one of the co-authors,and the name should be labeled correctly as appears on PDF.The affiliation of“Yu-jun SHUAI”and“Chao HUANG”is“Department of Urology,Union Hospital,Tongji Medical College,Huazhong University of Science and Technology,Wuhan 430022,China”,and both of them should be labeled as 1,as correctively appears on PDF.展开更多
BACKGROUND As an active ingredient derived from Dioscorea zingiberensis C.H.Wright,deltonin has been reported to show anti-cancer effects in a variety of malignancies.AIM To investigate the role and mechanism of actio...BACKGROUND As an active ingredient derived from Dioscorea zingiberensis C.H.Wright,deltonin has been reported to show anti-cancer effects in a variety of malignancies.AIM To investigate the role and mechanism of action of deltonin in promoting gastric carcinoma(GC)cell apoptosis and chemosensitivity to cisplatin.METHODS The GC cell lines AGS,HGC-27,and MKN-45 were treated with deltonin and then subjected to flow cytometry and 3-(4,5-dimethylthiazol-2-yl)-3,5-diphenyltet-razolium bromide assays for cell apoptosis and viability determination.Western blot analysis was conducted to examine alterations in the expression of apoptosis-related proteins(Bax,Bid,Bad,and Fas),DNA repair-associated proteins(Rad51 and MDM2),and phosphatidylinositol 3-kinase/protein kinase B/mammalian target of the rapamycin(PI3K/AKT/mTOR)and p38-mitogen-activated protein kinase(MAPK)axis proteins.Additionally,the influence of deltonin on GC cell chemosensitivity to cisplatin was evaluated both in vitro and in vivo.RESULTS Deltonin treatment weakened viability,enhanced apoptosis,and dampened DNA repair in GC cell lines in a dose-dependent pattern.Furthermore,deltonin mitigated PI3K,AKT,mTOR,and p38-MAPK phosphorylation.HS-173,an inhibitor of PI3K,attenuated GC cell viability and abolished deltonin inhibition of GC cell viability and PI3K/AKT/mTOR and p38-MAPK pathway activation.Deltonin also promoted the chemosensitivity of GC cells to cisplatin via repressing GC cell proliferation and growth and accelerating apoptosis.CONCLUSION Deltonin can boost the chemosensitivity of GC cells to cisplatin via inactivating p38-MAPK and PI3K/AKT/mTOR signaling.展开更多
Background: Resistance to cisplatin (DDP) leads to poor prognosis in patients with Lung Adenocarcinoma (LUAD) and limits its clinical application. It has been confirmed that autophagy promotes chemoresistance and, the...Background: Resistance to cisplatin (DDP) leads to poor prognosis in patients with Lung Adenocarcinoma (LUAD) and limits its clinical application. It has been confirmed that autophagy promotes chemoresistance and, therefore, novel strategies to reverse chemoresistance by regulating autophagy are desperately needed. Methods: The differentially expressed lncRNAs (DElncRNAs), miRNAs (DEmiRNAs), and mRNAs (DEmRNAs) between A549 and A549/DDP cell lines were identified using the limma package in R, after gene expression profiles were obtained from Gene Expression Omnibus (GEO) database. By combining Autophagy-Related Genes (ARGs) from Human Autophagy Database (HADb), the interactions lncRNA-miRNAs and the interactions miRNAs-mRNAs respectively predicted by miRcode and miRDB/Targetscan database, the autophagy-related ceRNA network was constructed. Then, extraction of ceRNA subnetwork and Cox regression analyses were performed. A prognosis-related ceRNA subnetwork was constructed, and the upstream Transcription Factors (TFs) regulating lncRNAs were predicted by the JASPAR database. Finally, the expression patterns of candidate genes were further verified by quantitative real-time polymerase chain reaction (qRT-PCR) experiments. Results: A total of 3179 DEmRNAs, 180 DEmiRNAs, and 160 DElncRNAs were identified, and 35 DEmRNAs were contained in the HADb. Based on the ceRNA hypothesis, we established a ceRNA network, including 10 autophagy-related DEmRNAs, 9 DEmiRNAs, and 14 DElncRNAs. Then, LINC00520, miR-181d, and BCL2 were identified to construct a risk score model, which was confirmed to be a well-predicting prognostic factor. Furthermore, 5 TF ZNF family members were predicted to regulate LINC00520, whereas the RT-PCR results showed that the 5 ZNFs were consistent with the bioinformatics analysis. Finally, a ZNF regulatory LINC00520/miR-181d/BCL2 ceRNA subnetwork was constructed. Conclusions: An ZNFs/LINC00520/miR-181d/BCL2 axis as a novel network in DDP-resistant LUAD has been constructed successfully, which may provide potential therapeutic targets for LUAD.展开更多
Background:Cisplatin is a chemotherapeutic agent commonly used clinically for the treatment of various human cancers.Patients often reduce the use of cisplatin due to its side effects,which in turn affects its treatme...Background:Cisplatin is a chemotherapeutic agent commonly used clinically for the treatment of various human cancers.Patients often reduce the use of cisplatin due to its side effects,which in turn affects its treatment.This study explored the mechanism of action of safflower extract as an adjuvant traditional Chinese medicine for chemotherapy.Methods:Primary human follicle dermal papilla cells(HFDPCs)were used as target cells for cisplatininduced damage to hair cells.Western blotting was used to investigate the molecular targets of cisplatin and safflower extract in causing HFDPCs damage.Cell survival and cell cycle were analyzed by mitochondrial staining reagent WST-1 and propidium iodide.Results:Cisplatin could reduce the viability of HFDPCs without causing cell death.Cisplatin increased the level of phospho-Rad17 in HFDPCs and activated the Chk1/Cdc25C signaling to reduce the expression of Cdc2 protein,thereby arresting the cells in the G2/M phase.The combination of safflower extract and the flavonoids could effectively inhibit the signal transduction of Rad17/Chk1/Cdc25 in cisplatin-treated cells and reduce the cell population in the G2/M phase.Finally,we also confirmed that safflower extract could effectively inhibit the damage to HFDPCs caused by cisplatin,mainly at the level of reducing the DNA damage caused by cisplatin.Conclusions:Safflower extract can be used as an adjuvant Chinese medicine for chemotherapy to reduce the damage caused by chemotherapy to normal hair follicle cells.展开更多
Background:Theanine,was natural compounds,has been employed in antibacterial,antineoplastic,promotion of hair growth,therapy of poliosis,and removing pattogenic heat from the blood and toxic material from the body for...Background:Theanine,was natural compounds,has been employed in antibacterial,antineoplastic,promotion of hair growth,therapy of poliosis,and removing pattogenic heat from the blood and toxic material from the body for centuries.However,few reports focused on the treatment by theanine combined with chemotherapy in triple negative breast cancer.Methods:Our study aimed to evaluate and compare the molecular and cellular effects of theanine in combination with cisplatin in triple negative breast cancer lines MDA-MB-231.The 50%inhibitory concentration and cell viability were determined by the cell counting kit-8 assay.Meanwhile,wound healing and transwell assays were used to evaluate the effect of theanine combination with cisplatin on triple negative breast cancer(TNBC)cell metastasis.Moreover,the label-free proteomic method was available to explore the molecular mechanism of theanine combination with cisplatin on TNBC cells.What’s more,reverse transcription-polymerase chain reaction and western blotting were carried out to evaluate the related protein and mRNA alteration in the Akt signaling pathway.Results:With theanine added,the inhibitory effect of cisplatin on cell proliferation and metastasis was significantly improved.Meanwhile,with the increase of theanine concentration,the anti-tumor effect of the combination group was also significantly improved.Afterward,label-free proteomics analysis showed that theanine combined with cisplatin could significantly activate the Akt signaling pathway,thus improving the anti-tumor effect of cisplatin.Finally,reverse transcription-polymerase chain reaction and western blotting experiment showed that the combination of cisplatin with theanine induced the greatest down-regulation of phosphorylated Akt expression.Conclusion:All in all,combining theanine with appears to be a promising strategy for the effective treatment of TNBC in the prospective application which merits further clinical investigation.展开更多
Objective Cisplatin(CDDP)-based chemotherapy is a first-line,drug regimen for muscle-invasive bladder cancer(BC)and metastatic bladder cancer.Clinically,resistance to CDDP restricts the clinical benefit of some bladde...Objective Cisplatin(CDDP)-based chemotherapy is a first-line,drug regimen for muscle-invasive bladder cancer(BC)and metastatic bladder cancer.Clinically,resistance to CDDP restricts the clinical benefit of some bladder cancer patients.AT-rich interaction domain 1A(ARID1A)gene mutation occurs frequently in bladder cancer;however,the role of CDDP sensitivity in BC has not been studied.Methods We established ARID1A knockout BC cell lines using CRISPR/Cas9 technology.IC50 determination,flow cytometry analysis of apoptosis,and tumor xenograft assays were performed to verify changes in the CDDP sensitivity of BC cells losing ARID1A.qRT-PCR,Western blotting,RNA interference,bioinformatic analysis,and ChIP-qPCR analysis were performed to further explore the potential mechanism of ARID1A inactivation in CDDP sensitivity in BC.Results It was found that ARID1A inactivation was associated with CDDP resistance in BC cells.Mechanically,loss of ARID1A promoted the expression of eukaryotic translation initiation factor 4A3(EIF4A3)through epigenetic regulation.Increased expression of EIF4A3 promoted the expression of hsa_circ_0008399(circ0008399),a novel circular RNA(circRNA)identified in our previous study,which,to some extent,showed that ARID1A deletion caused CDDP resistance through the inhibitory effect of circ0008399 on the apoptosis of BC cells.Importantly,EIF4A3-IN-2 specifically inhibited the activity of EIF4A3 to reduce circ0008399 production and restored the sensitivity of ARID1A inactivated BC cells to CDDP.Conclusion Our research deepens the understanding of the mechanisms of CDDP resistance in BC and elucidates a potential strategy to improve the efficacy of CDDP in BC patients with ARID1A deletion through combination therapy targeting EIF4A3.展开更多
[Objectives]This study was conducted to investigate the effects of different concentrations of cisplatin and metformin on the growth and proliferation of nasopharyngeal carcinoma SUNE-1 cells.[Methods]The concentratio...[Objectives]This study was conducted to investigate the effects of different concentrations of cisplatin and metformin on the growth and proliferation of nasopharyngeal carcinoma SUNE-1 cells.[Methods]The concentrations of cisplatin were set as 2.5,5.0,10.0,25.0,40.0μg/mL,and those of metformin were set as 0.625,1.25,2.5,5,10,and 20 mmol/L.After 48 h of intervention in nasopharyngeal carcinoma SUNE-1 cells,the proliferation inhibitory rate and the median inhibitory concentration(IC_(50))of SUNE-1 cells were measured by the CCK-8 method.[Results]It was found that different concentrations of cisplatin and metformin all had an inhibitory effect on the proliferation of SUNE-1 cells,and the inhibitory effect became more significant with the increase of concentration.The IC_(50)values of cisplatin and metformin were 43.57μg/mL and 6.855 mmol/L,respectively.[Conclusions]Cisplatin and metformin inhibited the proliferation of SUNE-1 cells in a concentration-dependent manner,providing a theoretical guidance for the clinical treatment of nasopharyngeal carcinoma.展开更多
Objective:To investigate the effect of mir-3168 on the malignant transformation and cisplatin resistance of AGS and AGS/DDP gastric cancer cells,and to verify its target gene.Methods:The expression of mir-3168 in AGS ...Objective:To investigate the effect of mir-3168 on the malignant transformation and cisplatin resistance of AGS and AGS/DDP gastric cancer cells,and to verify its target gene.Methods:The expression of mir-3168 in AGS and AGS/DDP gastric cancer cells was detected by qPCR,and mir-3168 mimic,inhibitor and negative control were synthesized.They were transfected into AGS and AGS/DDP gastric cancer cells,respectively.The expression of mir-3168 and TP53 mRNA was detected by qPCR.Cell viability was detected by CCK8 under gradient cisplatin treatment and non treatment,apoptosis was detected by flow cytometry,cell invasion was detected by Transwell,and TP53 protein expression was detected by western blot,The database predicted the binding sites of mir-3168 and TP53.According to the binding sites,the double luciferase experiment was used to verify the binding of mir-3168 and TP53.Results:Compared with cisplatin sensitive gastric cancer cell AGS,mir-3168 was significantly overexpressed in cisplatin resistant gastric cancer cell AGS/DDP;mir-3168 mimic promotes cisplatin resistance,proliferation and invasion of AGS and AGS/DDP gastric cancer cells,and inhibits apoptosis of AGS and AGS/DDP gastric cancer cells;mir-3168 inhibitor inhibits cisplatin resistance,proliferation and invasion of AGS and AGS/DDP gastric cancer cells,and promotes apoptosis of AGS and AGS/DDP gastric cancer cells;mir-3168 mimic inhibits the expression of TP53 mRNA and protein,and mir-3168 inhibitor promotes the expression of TP53 mRNA and protein;Targetscan database predicted that there was a binding point between mir-3168 and TP53,and the double luciferase experiment suggested that mir-3168 was bound to TP53 through the predicted binding site.Conclusion:mir-3168 may promote the malignant transformation of AGS and AGS/DDP gastric cancer cells and cisplatin resistance by targeting TP53.展开更多
Background:Salvage treatment for locally recurrent nasopharyngeal carcinoma(NPC) is complicated and relatively limited.Radiotherapy,combined with effective concomitant chemotherapy,may improve clinical treatment outco...Background:Salvage treatment for locally recurrent nasopharyngeal carcinoma(NPC) is complicated and relatively limited.Radiotherapy,combined with effective concomitant chemotherapy,may improve clinical treatment outcomes.We conducted a phase Ⅱ randomized controlled trial to evaluate the efficacy of intensity-modulated radiotherapy with concomitant weekly cisplatin on locally recurrent NPC.Methods:Between April 2002 and January 2008,69 patients diagnosed with non-metastatic locally recurrent NPC were randomly assigned to either concomitant chemoradiotherapy group(n = 34) or radiotherapy alone group(n = 35).All patients received intensity-modulated radiotherapy.The radiotherapy dose for both groups was 60 Gy in 27 fractions for 37 days(range 23-53 days).The concomitant chemotherapy schedule was cisplatin 30 mg/m^2 by intravenous infusion weekly during radiotherapy.Results:The median follow-up period of all patients was 35 months(range 2-112 months).Between concomitant chemoradiotherapy and radiotherapy groups,there was only significant difference in the 3-year and 5-year overall survival(OS) rates(68.7%vs.42.2%,P = 0.016 and 41.8%vs.27.5%,P = 0.049,respectively).Subgroup analysis showed that concomitant chemoradiotherapy significantly improved the 5-year OS rate especially for patients in stage rT3-4(33.0%vs.13.2%,P = 0.009),stages Ⅲ-Ⅳ(34.3%vs.13.2%,P = 0.006),recurrence interval >30 months(49.0%vs.20.6%,P = 0.017),and tumor volume >26 cm^3(37.6%vs.0%,P = 0.006).Conclusion:Compared with radiotherapy alone,concomitant chemoradiotherapy can improve OS of the patients with locally recurrent NPC,especially those with advanced T category(rT3-4) and stage(lll-IV) diseases,recurrence intervals >30 months,and tumor volume >26 cm^3.展开更多
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.
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.
基金financially supported by grants from the National Natural Science Foundation of China(82170873,81871095)the National Key R&D Program of China(2018YFC2000304)+1 种基金the Tsinghua Precision Medicine Foundation(10001020132)the Tsinghua University Spring Breeze Fund(20211080005)。
文摘De spite cisplatin has been widely used in the treatment of various cancers,the noteworthy nephrotoxicity greatly constrained its clinical value.For this reason,finding novel targeted therapies to attenuate the nephrotoxicity of cisplatin should be pretty significant.Our previous study found that histone deacetylase sirtuin 6(SIRT6)could be an ideal target for the treatment of cisplatin-induced acute kidney injury.In this study,we explored the protective effects of ellagic acid,a natural polyphenol compound that activates SIRT6,on cisplatin-induced nephrotoxicity.Pre-treatment of ellagic acid attenuated cytotoxicity of cisplatin in primary renal cells and TCMK-1 cells.Moreover,ellagic acid ameliorated renal dysfunction,apoptosis and fibrosis induced by cisplatin in mice.Furthermore,ellagic acid reduced nephrotoxicity-associated inflammatory factor interleukin(IL)-1βand IL-6 expression both in vitro and in vivo.Mechanistically,ellagic acid reversed cisplatin-reduced SIRT6 expression and diminished cisplatin-induced tumor necrosis factor(TNF)-αexpression.And SIRT6 knockdown abrogated the protective effects of ellagic acid on cisplatin-induced cell apoptosis,indicating the renal-protective effects of ellagic acid are mainly dependent on ellagic acid-mediated SIRT6 activation.Our results provide preclinical rationale for using ellagic acid as a feasible and promising agent to ameliorate cisplatin-induced acute kidney injury,and support ellagic acid as a potential adjunctive therapy for future cancer treatment.
基金supported by the National Key Research and Development Program of China(Grant Nos.2018YFC1003703 and 2018YFC1004203)the National Natural Science Foundation of China(Grant No.31871513).
文摘Anti-cancer therapy often causes premature ovarian insufficiency and infertility as the ovarian follicle reserve is extremely sensitive to chemotherapy drugs,such as cisplatin.Various fertility preservation methods have been explored for women,especially prepubertal girls undergoing radiotherapy and chemotherapy due to cancer.In recent years,mesenchymal stem cell-derived exosomes(MSC-exos)have been reported to play an important role in tissue repair and the treatment of various diseases.In the current study,we observed that human umbilical cord-derived MSC-exos(hucMSC-exos)after short-term culture improved follicular survival and development while receiving cisplatin treatment.Moreover,intravenous injection of hucMSC-exos improved ovarian function and ameliorated inflammatory environment within the ovary.The underlying mechanism of hucMSC-exos on fertility preservation was associated with the down-regulation of p53-related apoptosis and their anti-inflammatory function.Based on these findings,we propose that hucMSC-exos may be a potential approach to improve fertility in women diagnosed with cancer.
基金funded by the Jiangsu Medical Scientific Research Project of Jiangsu Health Commission(to Q.Y.)the 789 Outstanding Talent Program of SAHNMU(Grant No.789ZYRC 202070102 to Q.Y.)+1 种基金the Guangzhou Key Medical Discipline Construction Project(to Q.Y.)the National Natural Science Foundation of China(Grant Nos.81870409 and 81671543 to Q.Y.).
文摘Hepatoblastoma is the most frequent liver malignancy in children.HepG2 has been discovered as a hepatoblastoma-derived cell line and tends to form clumps in culture.Intriguingly,we observed that the addition of calcium ions reduced cell clumping and disassociated HepG2 cells.The calcium signal is in connection with a series of processes critical in the tumorigenesis.Here,we demonstrated that extracellular calcium ions induced morphological changes and enhanced the epithelial-mesenchymal transition in HepG2 cells.Mechanistically,calcium ions promoted HepG2 proliferation and migration by up-regulating the phosphorylation levels of focal adhesion kinase(FAK),protein kinase B,and p38 mitogen-activated protein kinase.The inhibitor of FAK or Ca2+/calmodulin-dependent kinaseⅡ(CaMKⅡ)reversed the Ca2+-induced effects on HepG2 cells,including cell proliferation and migration,epithelial-mesenchymal transition protein expression levels,and phosphorylation levels of FAK and protein kinase B.Moreover,calcium ions decreased HepG2 cells'sensitivity to cisplatin.Furthermore,we found that the expression levels of FAK and CaMKⅡwere increased in hepatoblastoma.The group with high expression levels of FAK and CaMKⅡexhibited significantly lower ImmunoScore as well as CD8+T and NK cells.The expression of CaMKⅡwas positively correlated with that of PDCD1 and LAG3.Correspondingly,the expression of FAK was negatively correlated with that of TNFSF9,TNFRSF4,and TNFRSF18.Collectively,extracellular calcium accelerates HepG2 cell proliferation and migration via FAK and CaMKⅡand enhances cisplatin resistance.FAK and CaMKⅡshape immune cell infiltration and responses in tumor microenvironments,thereby serving as potential targets for hepatoblastoma.
基金supported by the Scientific Research Plan of Department of Education of Hubei Province(No.B2021021).
文摘Objective Cisplatin is the first-line treatment for breast cancer,but it faces challenges of drug resistance.This study investigated new molecular mechanisms underlying cisplatin resistance in breast cancer.Methods We analyzed sequencing data from the TCGA database to identify potential associations between transmembrane emp24 protein transport domain containing 2(TMED2)and breast cancer.Western blotting,real-time PCR,CCK-8,and TUNEL assays were used to measure the effects and molecular mechanism of TMED2 on cisplatin resistance in MCF-7 and MDA-MB-231 cell lines.Results TMED2 was overexpressed in breast cancer and associated with poor prognosis.TMED2 increased cisplatin resistance in breast cancer cells in vitro via promoting ubiquitination of Kelch-like ECH-associated protein 1(KEAP1),relieving inhibition of KEAP1 on nuclear factor erythroid 2-related factor 2(Nrf2),and increasing expression of downstream drug resistance related genes,such as heme oxygenase 1(HO-1)and NAD(P)H quinone oxidoreductase 1(NQO1).Conclusion We identified a new molecular mechanism by which TMED2 affects cisplatin resistance in breast cancer.Our results provide theoretical guidance for future clinical applications.
基金The authors would like to extend their sincere appreciation to the Researchers Supporting Project Number(RSPD2023R986)King Saud University,Riyadh,Saudi Arabia.
文摘The low survival rate of Kidney renal clear cell carcinoma(KIRC)patients is largely attributed to cisplatin resistance.Rather than focusing solely on individual proteins,exploring protein-protein interactions could offer greater insight into drug resistance.To this end,a series of in silico and in vitro experiments were conducted to identify hub genes in the intricate network of cisplatin resistance-related genes in KIRC chemotherapy.The genes involved in cisplatin resistance across KIRC were retrieved from the National Center for Biotechnology Information(NCBI)database using search terms as“Kidney renal clear cell carcinoma”and“Cisplatin resistance”.The genes retrieved were analyzed for hub gene identification using the STRING database and Cytoscape tool.Expression and promoter methylation profiling of the hub genes was done using UALCAN,GEPIA,OncoDB,and HPA databases.Mutational,survival,functional enrichment,immune cell infiltration,and drug prediction analyses of the hub genes were performed using the cBioPortal,GEPIA,GSEA,TIMER,and DrugBank databases.Lastly,expression and methylation levels of the hub genes were validated on two cisplatin-resistant RCC cell lines(786-O and A-498)and a normal renal tubular epithelial cell line(HK-2)using two high throughput techniques,including targeted bisulfite sequencing(bisulfite-seq)and RT-qPCR.A total of 124 genes were identified as being associated with cisplatin resistance in KIRC.Out of these genes,MCL1,IGF1R,CCND1,and PTEN were identified as hub genes and were found to have significant(p<0.05)variations in their mRNA and protein expressions and effects on the overall survival(OS)of the KIRC patients.Moreover,an aberrant promoter methylation pattern was found to be associated with the dysregulation of the hub genes.In addition to this,hub genes were also linked with different cisplatin resistance-causing pathways.Thus,hub genes can be targeted with Alvocidib,Estradiol,Tretinoin,Capsaicin,Dronabinol,Metribolone,Calcitriol,Acetaminophen,Acitretin,Cyclosporine,Azacitidine,Genistein,and Resveratrol drugs.As the pathogenesis of KIRC is complex,targeting hub genes and associated pathways involved in cisplatin resistance could bring a milestone change in the drug discovery and management of drug resistance,which might uplift overall survival among KIRC patients.
基金supported by grants from the National Natural Science Foundation of China(Grant Nos.:82271158,82192865,and 82071045)Wenzhou Municipal Science and Technology Research Program(Grant No.:2021Y0681).
文摘This study aimed to evaluate the therapeutic potential of inhibiting protein arginine methyltransferase 5(PRMT5)in cisplatin-induced hearing loss.The effects of PRMT5 inhibition on cisplatin-induced auditory injury were determined using immunohistochemistry,apoptosis assays,and auditory brainstem response.The mechanism of PRMT5 inhibition on hair cell survival was assessed using RNA-seq and Cleavage Under Targets and Tagment-quantitative polymerase chain reaction(CUT&Tag-qPCR)analyses in the HEI-OC1 cell line.Pharmacological inhibition of PRMT5 significantly alleviated cisplatin-induced damage to hair cells and spiral ganglion neurons in the cochlea and decreased apoptosis by protecting mitochondrial function and preventing the accumulation of reactive oxygen species.CUT&Tag-qPCR analysis demonstrated that inhibition of PRMT5 in HEI-OC1 cells reduced the accumulation of H4R3me2s/H3R8me2s marks at the promoter region of the Pik3ca gene,thus activating the expression of Pik3ca.These findings suggest that PRMT5 inhibitors have strong potential as agents against cisplatininduced ototoxicity and can lay the foundation for further research on treatment strategies of hearing loss.
文摘The original version of this article was revised due to production error by the vendor.The author“Hua-min DING”is one of the co-authors,and the name should be labeled correctly as appears on PDF.The affiliation of“Yu-jun SHUAI”and“Chao HUANG”is“Department of Urology,Union Hospital,Tongji Medical College,Huazhong University of Science and Technology,Wuhan 430022,China”,and both of them should be labeled as 1,as correctively appears on PDF.
文摘BACKGROUND As an active ingredient derived from Dioscorea zingiberensis C.H.Wright,deltonin has been reported to show anti-cancer effects in a variety of malignancies.AIM To investigate the role and mechanism of action of deltonin in promoting gastric carcinoma(GC)cell apoptosis and chemosensitivity to cisplatin.METHODS The GC cell lines AGS,HGC-27,and MKN-45 were treated with deltonin and then subjected to flow cytometry and 3-(4,5-dimethylthiazol-2-yl)-3,5-diphenyltet-razolium bromide assays for cell apoptosis and viability determination.Western blot analysis was conducted to examine alterations in the expression of apoptosis-related proteins(Bax,Bid,Bad,and Fas),DNA repair-associated proteins(Rad51 and MDM2),and phosphatidylinositol 3-kinase/protein kinase B/mammalian target of the rapamycin(PI3K/AKT/mTOR)and p38-mitogen-activated protein kinase(MAPK)axis proteins.Additionally,the influence of deltonin on GC cell chemosensitivity to cisplatin was evaluated both in vitro and in vivo.RESULTS Deltonin treatment weakened viability,enhanced apoptosis,and dampened DNA repair in GC cell lines in a dose-dependent pattern.Furthermore,deltonin mitigated PI3K,AKT,mTOR,and p38-MAPK phosphorylation.HS-173,an inhibitor of PI3K,attenuated GC cell viability and abolished deltonin inhibition of GC cell viability and PI3K/AKT/mTOR and p38-MAPK pathway activation.Deltonin also promoted the chemosensitivity of GC cells to cisplatin via repressing GC cell proliferation and growth and accelerating apoptosis.CONCLUSION Deltonin can boost the chemosensitivity of GC cells to cisplatin via inactivating p38-MAPK and PI3K/AKT/mTOR signaling.
文摘Background: Resistance to cisplatin (DDP) leads to poor prognosis in patients with Lung Adenocarcinoma (LUAD) and limits its clinical application. It has been confirmed that autophagy promotes chemoresistance and, therefore, novel strategies to reverse chemoresistance by regulating autophagy are desperately needed. Methods: The differentially expressed lncRNAs (DElncRNAs), miRNAs (DEmiRNAs), and mRNAs (DEmRNAs) between A549 and A549/DDP cell lines were identified using the limma package in R, after gene expression profiles were obtained from Gene Expression Omnibus (GEO) database. By combining Autophagy-Related Genes (ARGs) from Human Autophagy Database (HADb), the interactions lncRNA-miRNAs and the interactions miRNAs-mRNAs respectively predicted by miRcode and miRDB/Targetscan database, the autophagy-related ceRNA network was constructed. Then, extraction of ceRNA subnetwork and Cox regression analyses were performed. A prognosis-related ceRNA subnetwork was constructed, and the upstream Transcription Factors (TFs) regulating lncRNAs were predicted by the JASPAR database. Finally, the expression patterns of candidate genes were further verified by quantitative real-time polymerase chain reaction (qRT-PCR) experiments. Results: A total of 3179 DEmRNAs, 180 DEmiRNAs, and 160 DElncRNAs were identified, and 35 DEmRNAs were contained in the HADb. Based on the ceRNA hypothesis, we established a ceRNA network, including 10 autophagy-related DEmRNAs, 9 DEmiRNAs, and 14 DElncRNAs. Then, LINC00520, miR-181d, and BCL2 were identified to construct a risk score model, which was confirmed to be a well-predicting prognostic factor. Furthermore, 5 TF ZNF family members were predicted to regulate LINC00520, whereas the RT-PCR results showed that the 5 ZNFs were consistent with the bioinformatics analysis. Finally, a ZNF regulatory LINC00520/miR-181d/BCL2 ceRNA subnetwork was constructed. Conclusions: An ZNFs/LINC00520/miR-181d/BCL2 axis as a novel network in DDP-resistant LUAD has been constructed successfully, which may provide potential therapeutic targets for LUAD.
基金supported by the Taipei Tzu Chi Hospital through grants from the Buddhist Tzu Chi Medical Foundation under the Numbers TCRD-TPE-110-13 and TCRD-TPE-111-23,Taipei,Taiwan.
文摘Background:Cisplatin is a chemotherapeutic agent commonly used clinically for the treatment of various human cancers.Patients often reduce the use of cisplatin due to its side effects,which in turn affects its treatment.This study explored the mechanism of action of safflower extract as an adjuvant traditional Chinese medicine for chemotherapy.Methods:Primary human follicle dermal papilla cells(HFDPCs)were used as target cells for cisplatininduced damage to hair cells.Western blotting was used to investigate the molecular targets of cisplatin and safflower extract in causing HFDPCs damage.Cell survival and cell cycle were analyzed by mitochondrial staining reagent WST-1 and propidium iodide.Results:Cisplatin could reduce the viability of HFDPCs without causing cell death.Cisplatin increased the level of phospho-Rad17 in HFDPCs and activated the Chk1/Cdc25C signaling to reduce the expression of Cdc2 protein,thereby arresting the cells in the G2/M phase.The combination of safflower extract and the flavonoids could effectively inhibit the signal transduction of Rad17/Chk1/Cdc25 in cisplatin-treated cells and reduce the cell population in the G2/M phase.Finally,we also confirmed that safflower extract could effectively inhibit the damage to HFDPCs caused by cisplatin,mainly at the level of reducing the DNA damage caused by cisplatin.Conclusions:Safflower extract can be used as an adjuvant Chinese medicine for chemotherapy to reduce the damage caused by chemotherapy to normal hair follicle cells.
基金the grants from Project of Schools Directly Under the Wenzhou Municipal Bureau(WX2022056).
文摘Background:Theanine,was natural compounds,has been employed in antibacterial,antineoplastic,promotion of hair growth,therapy of poliosis,and removing pattogenic heat from the blood and toxic material from the body for centuries.However,few reports focused on the treatment by theanine combined with chemotherapy in triple negative breast cancer.Methods:Our study aimed to evaluate and compare the molecular and cellular effects of theanine in combination with cisplatin in triple negative breast cancer lines MDA-MB-231.The 50%inhibitory concentration and cell viability were determined by the cell counting kit-8 assay.Meanwhile,wound healing and transwell assays were used to evaluate the effect of theanine combination with cisplatin on triple negative breast cancer(TNBC)cell metastasis.Moreover,the label-free proteomic method was available to explore the molecular mechanism of theanine combination with cisplatin on TNBC cells.What’s more,reverse transcription-polymerase chain reaction and western blotting were carried out to evaluate the related protein and mRNA alteration in the Akt signaling pathway.Results:With theanine added,the inhibitory effect of cisplatin on cell proliferation and metastasis was significantly improved.Meanwhile,with the increase of theanine concentration,the anti-tumor effect of the combination group was also significantly improved.Afterward,label-free proteomics analysis showed that theanine combined with cisplatin could significantly activate the Akt signaling pathway,thus improving the anti-tumor effect of cisplatin.Finally,reverse transcription-polymerase chain reaction and western blotting experiment showed that the combination of cisplatin with theanine induced the greatest down-regulation of phosphorylated Akt expression.Conclusion:All in all,combining theanine with appears to be a promising strategy for the effective treatment of TNBC in the prospective application which merits further clinical investigation.
基金This work was supported by grants from the National Natural Science Foundation of China(No.81974396,No.81874091,No.82072840,and No.82102734)the Natural Science Foundation of Hubei Province(No.2020CFB829)the Health Commission of Hubei Province Scientific Research Project(No.WJ2021F081).
文摘Objective Cisplatin(CDDP)-based chemotherapy is a first-line,drug regimen for muscle-invasive bladder cancer(BC)and metastatic bladder cancer.Clinically,resistance to CDDP restricts the clinical benefit of some bladder cancer patients.AT-rich interaction domain 1A(ARID1A)gene mutation occurs frequently in bladder cancer;however,the role of CDDP sensitivity in BC has not been studied.Methods We established ARID1A knockout BC cell lines using CRISPR/Cas9 technology.IC50 determination,flow cytometry analysis of apoptosis,and tumor xenograft assays were performed to verify changes in the CDDP sensitivity of BC cells losing ARID1A.qRT-PCR,Western blotting,RNA interference,bioinformatic analysis,and ChIP-qPCR analysis were performed to further explore the potential mechanism of ARID1A inactivation in CDDP sensitivity in BC.Results It was found that ARID1A inactivation was associated with CDDP resistance in BC cells.Mechanically,loss of ARID1A promoted the expression of eukaryotic translation initiation factor 4A3(EIF4A3)through epigenetic regulation.Increased expression of EIF4A3 promoted the expression of hsa_circ_0008399(circ0008399),a novel circular RNA(circRNA)identified in our previous study,which,to some extent,showed that ARID1A deletion caused CDDP resistance through the inhibitory effect of circ0008399 on the apoptosis of BC cells.Importantly,EIF4A3-IN-2 specifically inhibited the activity of EIF4A3 to reduce circ0008399 production and restored the sensitivity of ARID1A inactivated BC cells to CDDP.Conclusion Our research deepens the understanding of the mechanisms of CDDP resistance in BC and elucidates a potential strategy to improve the efficacy of CDDP in BC patients with ARID1A deletion through combination therapy targeting EIF4A3.
基金Supported by Fujian Provincial Young and Middle-aged Teacher Education and Scientific Research Project(JAT200706)Innovation and Entrepreneurship Training Program for College Students of Xiamen Medical College(X202112631068)。
文摘[Objectives]This study was conducted to investigate the effects of different concentrations of cisplatin and metformin on the growth and proliferation of nasopharyngeal carcinoma SUNE-1 cells.[Methods]The concentrations of cisplatin were set as 2.5,5.0,10.0,25.0,40.0μg/mL,and those of metformin were set as 0.625,1.25,2.5,5,10,and 20 mmol/L.After 48 h of intervention in nasopharyngeal carcinoma SUNE-1 cells,the proliferation inhibitory rate and the median inhibitory concentration(IC_(50))of SUNE-1 cells were measured by the CCK-8 method.[Results]It was found that different concentrations of cisplatin and metformin all had an inhibitory effect on the proliferation of SUNE-1 cells,and the inhibitory effect became more significant with the increase of concentration.The IC_(50)values of cisplatin and metformin were 43.57μg/mL and 6.855 mmol/L,respectively.[Conclusions]Cisplatin and metformin inhibited the proliferation of SUNE-1 cells in a concentration-dependent manner,providing a theoretical guidance for the clinical treatment of nasopharyngeal carcinoma.
基金This study was supported by National Natural Science Foundation of China(81960303)Youjiang Medical College for Nationalities Affiliated Hospital(R202011710)+6 种基金Youjiang Medical College for Nationalities Affiliated Hospital,Youjiang Key Talents Research Project(Y20212603)Guangxi Key Laboratory of Molecular Pathology of Hepatobiliary Diseases,Affiliated Hospital of Youjiang Medical College for Nationalities(GxZDSYs-009)Scientific Research and Technology Development Program of Baise City(Baike 20213301)Scientific Research and Technology Development Program of Baise City(Baike 20213242)Self-funded research project of Health Commission of Guangxi Zhuang Autonomous Region(20190953)Self-funded research Project of Administration of Traditional Chinese Medicine of Guangxi Zhuang Autonomous Region(GXZYL20220304)Guangxi University Young and Middle-aged Teachers Basic Research Ability Improvement Project(2021KY0538)。
文摘Objective:To investigate the effect of mir-3168 on the malignant transformation and cisplatin resistance of AGS and AGS/DDP gastric cancer cells,and to verify its target gene.Methods:The expression of mir-3168 in AGS and AGS/DDP gastric cancer cells was detected by qPCR,and mir-3168 mimic,inhibitor and negative control were synthesized.They were transfected into AGS and AGS/DDP gastric cancer cells,respectively.The expression of mir-3168 and TP53 mRNA was detected by qPCR.Cell viability was detected by CCK8 under gradient cisplatin treatment and non treatment,apoptosis was detected by flow cytometry,cell invasion was detected by Transwell,and TP53 protein expression was detected by western blot,The database predicted the binding sites of mir-3168 and TP53.According to the binding sites,the double luciferase experiment was used to verify the binding of mir-3168 and TP53.Results:Compared with cisplatin sensitive gastric cancer cell AGS,mir-3168 was significantly overexpressed in cisplatin resistant gastric cancer cell AGS/DDP;mir-3168 mimic promotes cisplatin resistance,proliferation and invasion of AGS and AGS/DDP gastric cancer cells,and inhibits apoptosis of AGS and AGS/DDP gastric cancer cells;mir-3168 inhibitor inhibits cisplatin resistance,proliferation and invasion of AGS and AGS/DDP gastric cancer cells,and promotes apoptosis of AGS and AGS/DDP gastric cancer cells;mir-3168 mimic inhibits the expression of TP53 mRNA and protein,and mir-3168 inhibitor promotes the expression of TP53 mRNA and protein;Targetscan database predicted that there was a binding point between mir-3168 and TP53,and the double luciferase experiment suggested that mir-3168 was bound to TP53 through the predicted binding site.Conclusion:mir-3168 may promote the malignant transformation of AGS and AGS/DDP gastric cancer cells and cisplatin resistance by targeting TP53.
文摘Background:Salvage treatment for locally recurrent nasopharyngeal carcinoma(NPC) is complicated and relatively limited.Radiotherapy,combined with effective concomitant chemotherapy,may improve clinical treatment outcomes.We conducted a phase Ⅱ randomized controlled trial to evaluate the efficacy of intensity-modulated radiotherapy with concomitant weekly cisplatin on locally recurrent NPC.Methods:Between April 2002 and January 2008,69 patients diagnosed with non-metastatic locally recurrent NPC were randomly assigned to either concomitant chemoradiotherapy group(n = 34) or radiotherapy alone group(n = 35).All patients received intensity-modulated radiotherapy.The radiotherapy dose for both groups was 60 Gy in 27 fractions for 37 days(range 23-53 days).The concomitant chemotherapy schedule was cisplatin 30 mg/m^2 by intravenous infusion weekly during radiotherapy.Results:The median follow-up period of all patients was 35 months(range 2-112 months).Between concomitant chemoradiotherapy and radiotherapy groups,there was only significant difference in the 3-year and 5-year overall survival(OS) rates(68.7%vs.42.2%,P = 0.016 and 41.8%vs.27.5%,P = 0.049,respectively).Subgroup analysis showed that concomitant chemoradiotherapy significantly improved the 5-year OS rate especially for patients in stage rT3-4(33.0%vs.13.2%,P = 0.009),stages Ⅲ-Ⅳ(34.3%vs.13.2%,P = 0.006),recurrence interval >30 months(49.0%vs.20.6%,P = 0.017),and tumor volume >26 cm^3(37.6%vs.0%,P = 0.006).Conclusion:Compared with radiotherapy alone,concomitant chemoradiotherapy can improve OS of the patients with locally recurrent NPC,especially those with advanced T category(rT3-4) and stage(lll-IV) diseases,recurrence intervals >30 months,and tumor volume >26 cm^3.
