Cisplatin-induced activation of TGF-βsignaling contributes to drug resistance

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.

miR-125b reverses cisplatin resistance by regulating autophagy via targeting RORA/BNIP3L axis in lung adenocarcinoma

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.

TGF-β-regulated different iron metabolism processes in the development and cisplatin resistance of ovarian cancer

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.

Celecoxib enhances the response of tumor cells to cisplatin through upregulating PUMA in non–small cell lung cancer carrying wild-type p53

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.

Feasibility Study for Biweekly Administration of Cisplatin plus Vinorelbine as Adjuvant-Chemotherapy for Completely Resected Non-Small Cell Lung Cancer Patients in a Japanese Population

Purpose: To evaluate the feasibility of biweekly administration of cisplatin and vinorelbine as adjuvant chemotherapy for patients with completely resected non-small cell lung cancer (NSCLC). Patients and Methods: This was a single-arm, single-institutional study. Patients with completely resected NSCLC (p-Stage IB-IIIA) with no previous chemotherapy or radiotherapy were eligible. Simon’s optimal two-stage design was applied. Both cisplatin (50 mg/m2) and vinorelbine (25 mg/m2) were given on days 1 and 15, every 28 days. The primary endpoint of this study was the feasibility of this combination in the four cycles of treatment. Results: Twenty patients (19 lobectomies and 1 pneumonectomy) were enrolled in this study. 10 (50%) of patients had grade 3/4 neutropenia, and 3 (15%) had grade 3/4 anemia. Severe non-hematologic toxicities were uncommon in this series. No treatment-related death was encountered. 18 (90%) patients completed the planned 4 cycles of chemotherapy. The median intensity was 24.3 (range 18.1 to 25) mg/m2/week with an average of 23.6 (21 - 25) mg/m2/week cisplatin and 12.5 (range 10 to 12.5) mg/m2/week with an average of 12.3 (10 - 12.5) mg/m2/week vinorelbine. The median relative dose intensity of cisplatin was 97.5% (range 72.5% to 100%) with an average of 94.6% (72.5% - 100%) and that of vinorelbine was 100% (range 80% to 100%) with an average of 97.8% (80% - 100%). Conclusion: This regimen is feasible in the treatment of patients with completely resected NSCLC. A phase III trial is warranted to assess the efficacy of this regimen at promoting survival and preventing recurrence.

hucMSC-derived exosomes protect ovarian reserve and restore ovarian function in cisplatin treated mice

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.

TMED2 Induces Cisplatin Resistance in Breast Cancer via Targeting the KEAP1-Nrf2 Pathway

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.

Ellagic acid ameliorates cisplatin-induced acute kidney injury by regulating inflammation and SIRT6/TNF-α signaling

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.

Theanine combined with cisplatin inhibits the proliferation and metastasis of TNBC cells through Akt signaling pathway

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.

Effect of Intraperitoneal Administration of Paclitaxel Combined with Cisplatin in Treatment of Advanced Ovarian Cancer

Objective:To analyze the effect of intraperitoneal administration of paclitaxel combined with cisplatin in treatment of advanced ovarian cancer.Method:Fifty-four patients with advanced ovarian cancer in our hospital were randomly selected from the beginning of July 2018 to the end of June 2019.The principle of grouping was based on double-blind randomization method.In experimental group,27 patients were given intraperitoneal administration of paclitaxel combined with cisplatin.In control group,27 patients were given intravenous administration of paclitaxel combined with cisplatin.Clinical data of the two groups were compared.Results:Short-term clinical efficacy and T lymphocyte subsets of experimental group were significantly improved when compared with control group.The difference was significant(P<0.05).There was no significant difference in adverse reactions between the two groups(P>0.05).Conclusion:The effect of intraperitoneal administration of paclitaxel combined with cisplatin is ideal for treatment of advanced ovarian cancer patients.

Bioinformatics Identification of ZNFs/LINC00520/miR-181d/BCL2 Axis as a Novel Network in Cisplatin-Resistant Lung Adenocarcinoma Cells

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.

Low Complexity Detection Algorithms Based on ADMIN for Massive MIMO

This paper proposes the alternating direction method of multipliers-based infinity-norm(ADMIN) with threshold(ADMIN-T) and with percentage(ADMIN-P) detection algorithms,which make full use of the distribution of the signal to interference plus noise ratio(SINR) for an uplink massive MIMO system.The ADMIN-T and ADMIN-P detection algorithms are improved visions of the ADMIN detection algorithm,in which an appropriate SINR threshold in the ADMIN-T detection algorithm and a certain percentage in the ADMIN-P detection algorithm are designed to reduce the overall computational complexity.The detected symbols are divided into two parts by the SINR threshold which is based on the cumulative probability density function(CDF) of SINR and a percentage,respectively.The symbols in higher SINR part are detected by MMSE.The interference of these symbols is then cancelled by successive interference cancellation(SIC).Afterwards the remaining symbols with low SINR are iteratively detected by ADMIN.The simulation results show that the ADMIIN-T and the ADMIN-P detection algorithms provide a significant performance gain compared with some recently proposed detection algorithms.In addition,the computational complexity of ADMIN-T and ADMIN-P are significantly reduced.Furthermore,in the case of same number of transceiver antennas,the proposed algorithms have a higher performance compared with the case of asymmetric transceiver antennas.

Deciphering key genes involved in cisplatin resistance in kidney renal clear cell carcinoma through a combined in silico and in vitro approach

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.

Erratum to:ARID1A Inactivation Increases Expression of circ0008399 and Promotes Cisplatin Resistance in Bladder Cancer

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.

The Role for AVE0991 (MAS-Receptor Angiotensin II (1-7) Agonist) in Reducing Cisplatin-Induced Acute Kidney Injury on C57BL/6 Mice

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.

Elevated extracellular calcium ions accelerate the proliferation and migration of HepG2 cells and decrease cisplatin sensitivity

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.

Deltonin enhances gastric carcinoma cell apoptosis and chemosensitivity to cisplatin via inhibiting PI3K/AKT/mTOR and MAPK signaling

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.

Effects of Cisplatin and Metformin on Proliferation of Nasopharyngeal Carcinoma SUNE-1 Cells

[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.

mir-3168 targeted inhibition of TP53 promotes malignant transformation and cisplatin resistance of AGS and AGS/DDP gastric cancer cells

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.

Inhibition of histone methyltransferase PRMT5 attenuates cisplatininduced hearing loss through the PI3K/Akt-mediated mitochondrial apoptotic pathway

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.