AIM: To evaluate the dose-limiting toxicities(DLTs)and determine the maximum-tolerated dose(MTD) and recommended dose(RD) of combination chemotherapy with gemcitabine, cisplatin and S-1 which is an oral fluoropyrimidi...AIM: To evaluate the dose-limiting toxicities(DLTs)and determine the maximum-tolerated dose(MTD) and recommended dose(RD) of combination chemotherapy with gemcitabine, cisplatin and S-1 which is an oral fluoropyrimidine pro-drug in patients with advanced biliary tract cancer.METHODS: Patients with histologically or cytologically confirmed unresectable or recurrent biliary tract cancer were enrolled. The planned dose levels of gemcitabine(mg/m2), cisplatin(mg/m2), and S-1(mg/m2 per day) were as follows: level-1, 800/20/60;level 0, 800/25/60; level 1, 1000/25/60; and level 2,1000/25/80. In each cycle, gemcitabine and cisplatin were administered intravenously on days 1 and 15,and S-1 was administered orally twice daily on days 1to 7 and days 15 to 21, every 4 wk.RESULTS: Twelve patients were enrolled, and level0 was chosen as the starting dose. None of the first three patients had DLTs at level 0, and the dose was escalated to level 1. One of six patients had DLTs(grade 4 febrile neutropenia, leucopenia, and neutropenia; grade 3 thrombocytopenia) at level 1.We then proceeded to level 2. None of three patients had DLTs during the first cycle. Although the MTD was not determined, level 2 was designated at the RD for a subsequent phase Ⅱ study.CONCLUSION: The RD was defined as gemcitabine1000 mg/m2(days 1, 15), cisplatin 25 mg/m2(days1, 15), and S-1 80 mg/m2 per day(days 1-7, 15-21),every 4 weeks. A phase Ⅱ study is planned to evaluate the effectiveness of combination chemotherapy withgemcitabine, cisplatin, and S-1 in advanced biliary tract cancer.展开更多
Objective: To evaluate the feasibility of S-1 and high-dose cisplatin short hydration regimens for outpatients with unresectable metastatic gastric cancer. Methods: Data for individual outpatients treated in our insti...Objective: To evaluate the feasibility of S-1 and high-dose cisplatin short hydration regimens for outpatients with unresectable metastatic gastric cancer. Methods: Data for individual outpatients treated in our institution were retrospectively pooled to assess the feasibility of an S-1 and highdose cisplatin short hydration regimen (S-1: 80 to 120 mg on Days 1 to 21;cisplatin: 60 mg/m2?on Day 8, every 5 weeks), which included 2250 ml of intravenous fluids and 1000 ml oral hydration. Ten consecutive patients were treated with S-1 and high-dose cisplatin short hydration for unresectable metastatic gastric cancer from July 2011 to May 2012 and were included in the analysis. Results: With a median of 3.5 medication cycles, unscheduled admission occurred in two patients for 5 days each due to paralytic ileus and cerebral infarction. Four patients required dose reduction, in both S-1 and cisplatin in two patients, and in S-1 alone and cisplatin alone in one patient each. Renal function transiently declined after administration of cisplatin, but serum creatinine level and estimated glomerular filtration rate were both improved by the time of the next administration. Conclusion: This study suggests that an S-1 and high-dose cisplatin short hydration strategy for outpatients with unresectable metastatic gastric cancer might be feasible.展开更多
Background: Despite there are a few reports that assessed the S-1 + CDDP regimen with short hydration regimen for unresectable or metastatic gastric cancer, there is no consensus on the best regimen for short hydratio...Background: Despite there are a few reports that assessed the S-1 + CDDP regimen with short hydration regimen for unresectable or metastatic gastric cancer, there is no consensus on the best regimen for short hydration. The aim of study was to evaluate the safety and the efficacy of S-1 plus cisplatin doublet chemotherapy with short hydration. Methods: S-1 was administered orally (p.o.) twice daily for the first 3 weeks of a 5-week cycle. Dose of S-1 administered was calculated according to the body surface area. CDDP was given as an intravenous (i.v.) infusion of 60 mg/m2 on day 8 of each cycle. Patients received the total of 1900 ml infusion containing 1000 ml of acetate Ringer’s solution as pre- and post-hydraion. 300 ml of 20% mannitol was administered as a diuretic. Results: 35 patients with unresectable or recurrent gastric cancer were enrolled. The reasons for termination of S-1 + CDDP were as follows: 21 (63.6%) by progressive disease;12 (31.4%) by toxicity. Even though 12 of 35 patients (34.2%) were discontinued S-1 + CDDP chemotherapy, only one patient was discontinued by Grade 2 of increased creatinine. TTF (time to progression) was 174 days (3 - 586 days), and the median of the total number of treatment cycles of S-1 + CDDP was 3.31. Median overall survival, as secondary endpoint, was 518 days. Conclusions: Our study suggested that the short hydration regimen is as safe and efficient as the continuous hydration regimen.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
在Ce_(0.8)Cu_(0.2)O_(2)氧载体中添加不同质量S-1分子筛,并利用XRD、BET、XPS、SEM、TEM和CH4-TPR&CO_(2)-TPO等表征对氧载体的物化特性和反应性能进行了研究。考察了S-1分子筛添加量对Ce_(0.8)Cu_(0.2)O_(2)氧载体在化学链甲烷重...在Ce_(0.8)Cu_(0.2)O_(2)氧载体中添加不同质量S-1分子筛,并利用XRD、BET、XPS、SEM、TEM和CH4-TPR&CO_(2)-TPO等表征对氧载体的物化特性和反应性能进行了研究。考察了S-1分子筛添加量对Ce_(0.8)Cu_(0.2)O_(2)氧载体在化学链甲烷重整耦合CO_(2)还原反应中的性能的影响。与单纯的Ce_(0.8)Cu_(0.2)O_(2)氧载体相比,添加了0.3 g S-1分子筛后复合氧载体的比表面积明显增大,从15.44 m^(2)/g提高至73.27 m^(2)/g。同时热稳定性和结构稳定性也得到了很大的改善。添加了0.3 g S-1分子筛的复合氧载体CH4转化率由38.93%提升至56.03%,CO_(2)还原过程中CO产率由1.18 mmol/g增加至2.16 mmol/g。展开更多
Objective: To evaluate the role of class III β-tubulin (TUBB3), thymidylate synthase (TS), thymidine phosphorylase (TP), and excision repair cross-complementing group 1 (ERCC1) in clinical outcome of advanced gastric...Objective: To evaluate the role of class III β-tubulin (TUBB3), thymidylate synthase (TS), thymidine phosphorylase (TP), and excision repair cross-complementing group 1 (ERCC1) in clinical outcome of advanced gastric cancer patients receiving capecitabine plus paclitaxel or cisplatin. Methods: The clinical data and tumor specimens from 57 advanced gastric cancer patients receiving first-line capecitabine plus paclitaxel (cohort 1, n=36) and capecitabine plus cisplatin (cohort 2, n=21) were retrospectively collected, and TUBB3, TS, TP, and ERCC1 expressions were detected by real-time quantitative PCR. The associations between expressions of biomarkers and response or survival were analyzed statistically. Results: The median age of 57 patients was 57 years (range: 27–75 years) with 38 males and 19 females. Of all patients, the response rates of patients with high TP, low TP and high TS, low TS expressions were 57.1%, 27.6% (P=0.024), and 55.2%, 28.6% (P=0.042), respectively. Among cohort 1, the response rates and median overall survivals of patients with low and high TUBB3 expressions were 61.1% vs. 33.3% (P=0.095) and 13.8 months vs. 6.6 months (P=0.019), respectively; the response rate (87.5%) of patients with low TUBB3 and high TP expressions was higher than that (14.3%) of patients with high TUBB3 and low TP expressions (P=0.01). Among cohort 2, the response rates of patients with low ERCC1 and high ERCC1 expressions were 45.5% and 20.0% respectively (P=0.361). Conclusion: TUBB3, TS and TP expressions could predict the response of advanced gastric cancer patients receiving capecitabine-based and paclitaxel-based chemotherapy. These results will be further confirmed in future large samples.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
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
Objective:Gemcitabine plus nab-paclitaxel(GnP)is the standard first-line therapy for advanced pancreatic ductal adenocarcinoma(PDAC).S-1,an oral fluoropyrimidine derivative,as compared with gemcitabine,is non-inferior...Objective:Gemcitabine plus nab-paclitaxel(GnP)is the standard first-line therapy for advanced pancreatic ductal adenocarcinoma(PDAC).S-1,an oral fluoropyrimidine derivative,as compared with gemcitabine,is non-inferior in terms of overall survival(OS)and is associated with lower hematologic toxicity.Accordingly,S-1 is a convenient oral alternative treatment for advanced PDAC.This study was aimed at comparing the efficacy and safety of gemcitabine plus S-1(GS)vs.GnP as first-line chemotherapy for advanced PDAC.Methods:Patients with advanced PDAC who received first-line GS or GnP at the Peking Union Medical College Hospital between March 2011 and November 2022 were evaluated.Results:A total of 300 patients were assessed,of whom 84 received GS and 216 received GnP.The chemotherapy completion rate was higher with GS than GnP(50.0%vs.30.3%,P=0.0028).The objective response rate(ORR)was slightly higher(14.3%vs.9.7%,P=0.35),and the median OS was significantly longer(17.9 months vs.13.3 months,P=0.0078),in the GS group than the GnP group.However,the median progression-free survival(PFS)did not significantly differ between groups.Leukopenia risk was significantly lower in the GS group than the GnP group(14.9%vs.28.1%,P=0.049).Conclusions:As first-line chemotherapy for advanced PDAC,the GS regimen led to a significantly longer OS than the GnP regimen.The PFS,ORR,and incidence of severe adverse events were comparable between the GS and GnP groups.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
文摘AIM: To evaluate the dose-limiting toxicities(DLTs)and determine the maximum-tolerated dose(MTD) and recommended dose(RD) of combination chemotherapy with gemcitabine, cisplatin and S-1 which is an oral fluoropyrimidine pro-drug in patients with advanced biliary tract cancer.METHODS: Patients with histologically or cytologically confirmed unresectable or recurrent biliary tract cancer were enrolled. The planned dose levels of gemcitabine(mg/m2), cisplatin(mg/m2), and S-1(mg/m2 per day) were as follows: level-1, 800/20/60;level 0, 800/25/60; level 1, 1000/25/60; and level 2,1000/25/80. In each cycle, gemcitabine and cisplatin were administered intravenously on days 1 and 15,and S-1 was administered orally twice daily on days 1to 7 and days 15 to 21, every 4 wk.RESULTS: Twelve patients were enrolled, and level0 was chosen as the starting dose. None of the first three patients had DLTs at level 0, and the dose was escalated to level 1. One of six patients had DLTs(grade 4 febrile neutropenia, leucopenia, and neutropenia; grade 3 thrombocytopenia) at level 1.We then proceeded to level 2. None of three patients had DLTs during the first cycle. Although the MTD was not determined, level 2 was designated at the RD for a subsequent phase Ⅱ study.CONCLUSION: The RD was defined as gemcitabine1000 mg/m2(days 1, 15), cisplatin 25 mg/m2(days1, 15), and S-1 80 mg/m2 per day(days 1-7, 15-21),every 4 weeks. A phase Ⅱ study is planned to evaluate the effectiveness of combination chemotherapy withgemcitabine, cisplatin, and S-1 in advanced biliary tract cancer.
文摘Objective: To evaluate the feasibility of S-1 and high-dose cisplatin short hydration regimens for outpatients with unresectable metastatic gastric cancer. Methods: Data for individual outpatients treated in our institution were retrospectively pooled to assess the feasibility of an S-1 and highdose cisplatin short hydration regimen (S-1: 80 to 120 mg on Days 1 to 21;cisplatin: 60 mg/m2?on Day 8, every 5 weeks), which included 2250 ml of intravenous fluids and 1000 ml oral hydration. Ten consecutive patients were treated with S-1 and high-dose cisplatin short hydration for unresectable metastatic gastric cancer from July 2011 to May 2012 and were included in the analysis. Results: With a median of 3.5 medication cycles, unscheduled admission occurred in two patients for 5 days each due to paralytic ileus and cerebral infarction. Four patients required dose reduction, in both S-1 and cisplatin in two patients, and in S-1 alone and cisplatin alone in one patient each. Renal function transiently declined after administration of cisplatin, but serum creatinine level and estimated glomerular filtration rate were both improved by the time of the next administration. Conclusion: This study suggests that an S-1 and high-dose cisplatin short hydration strategy for outpatients with unresectable metastatic gastric cancer might be feasible.
文摘Background: Despite there are a few reports that assessed the S-1 + CDDP regimen with short hydration regimen for unresectable or metastatic gastric cancer, there is no consensus on the best regimen for short hydration. The aim of study was to evaluate the safety and the efficacy of S-1 plus cisplatin doublet chemotherapy with short hydration. Methods: S-1 was administered orally (p.o.) twice daily for the first 3 weeks of a 5-week cycle. Dose of S-1 administered was calculated according to the body surface area. CDDP was given as an intravenous (i.v.) infusion of 60 mg/m2 on day 8 of each cycle. Patients received the total of 1900 ml infusion containing 1000 ml of acetate Ringer’s solution as pre- and post-hydraion. 300 ml of 20% mannitol was administered as a diuretic. Results: 35 patients with unresectable or recurrent gastric cancer were enrolled. The reasons for termination of S-1 + CDDP were as follows: 21 (63.6%) by progressive disease;12 (31.4%) by toxicity. Even though 12 of 35 patients (34.2%) were discontinued S-1 + CDDP chemotherapy, only one patient was discontinued by Grade 2 of increased creatinine. TTF (time to progression) was 174 days (3 - 586 days), and the median of the total number of treatment cycles of S-1 + CDDP was 3.31. Median overall survival, as secondary endpoint, was 518 days. Conclusions: Our study suggested that the short hydration regimen is as safe and efficient as the continuous hydration regimen.
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.
文摘在Ce_(0.8)Cu_(0.2)O_(2)氧载体中添加不同质量S-1分子筛,并利用XRD、BET、XPS、SEM、TEM和CH4-TPR&CO_(2)-TPO等表征对氧载体的物化特性和反应性能进行了研究。考察了S-1分子筛添加量对Ce_(0.8)Cu_(0.2)O_(2)氧载体在化学链甲烷重整耦合CO_(2)还原反应中的性能的影响。与单纯的Ce_(0.8)Cu_(0.2)O_(2)氧载体相比,添加了0.3 g S-1分子筛后复合氧载体的比表面积明显增大,从15.44 m^(2)/g提高至73.27 m^(2)/g。同时热稳定性和结构稳定性也得到了很大的改善。添加了0.3 g S-1分子筛的复合氧载体CH4转化率由38.93%提升至56.03%,CO_(2)还原过程中CO产率由1.18 mmol/g增加至2.16 mmol/g。
基金supported by the National "863" High‐Tech Res & Dev Program of China (No. 2006AA02A402)Beijing Municipal Science & Technology Commission Program "Optimization of pharmacotherapy and individual selection in gastric cancer" (No D101100050010023)
文摘Objective: To evaluate the role of class III β-tubulin (TUBB3), thymidylate synthase (TS), thymidine phosphorylase (TP), and excision repair cross-complementing group 1 (ERCC1) in clinical outcome of advanced gastric cancer patients receiving capecitabine plus paclitaxel or cisplatin. Methods: The clinical data and tumor specimens from 57 advanced gastric cancer patients receiving first-line capecitabine plus paclitaxel (cohort 1, n=36) and capecitabine plus cisplatin (cohort 2, n=21) were retrospectively collected, and TUBB3, TS, TP, and ERCC1 expressions were detected by real-time quantitative PCR. The associations between expressions of biomarkers and response or survival were analyzed statistically. Results: The median age of 57 patients was 57 years (range: 27–75 years) with 38 males and 19 females. Of all patients, the response rates of patients with high TP, low TP and high TS, low TS expressions were 57.1%, 27.6% (P=0.024), and 55.2%, 28.6% (P=0.042), respectively. Among cohort 1, the response rates and median overall survivals of patients with low and high TUBB3 expressions were 61.1% vs. 33.3% (P=0.095) and 13.8 months vs. 6.6 months (P=0.019), respectively; the response rate (87.5%) of patients with low TUBB3 and high TP expressions was higher than that (14.3%) of patients with high TUBB3 and low TP expressions (P=0.01). Among cohort 2, the response rates of patients with low ERCC1 and high ERCC1 expressions were 45.5% and 20.0% respectively (P=0.361). Conclusion: TUBB3, TS and TP expressions could predict the response of advanced gastric cancer patients receiving capecitabine-based and paclitaxel-based chemotherapy. These results will be further confirmed in future large samples.
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.
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supported by grants from National High Level Hospital Clinical Research Funding(Grant Nos.2022-PUMCH-D-001 and 2022-PUMCH-A-213)。
文摘Objective:Gemcitabine plus nab-paclitaxel(GnP)is the standard first-line therapy for advanced pancreatic ductal adenocarcinoma(PDAC).S-1,an oral fluoropyrimidine derivative,as compared with gemcitabine,is non-inferior in terms of overall survival(OS)and is associated with lower hematologic toxicity.Accordingly,S-1 is a convenient oral alternative treatment for advanced PDAC.This study was aimed at comparing the efficacy and safety of gemcitabine plus S-1(GS)vs.GnP as first-line chemotherapy for advanced PDAC.Methods:Patients with advanced PDAC who received first-line GS or GnP at the Peking Union Medical College Hospital between March 2011 and November 2022 were evaluated.Results:A total of 300 patients were assessed,of whom 84 received GS and 216 received GnP.The chemotherapy completion rate was higher with GS than GnP(50.0%vs.30.3%,P=0.0028).The objective response rate(ORR)was slightly higher(14.3%vs.9.7%,P=0.35),and the median OS was significantly longer(17.9 months vs.13.3 months,P=0.0078),in the GS group than the GnP group.However,the median progression-free survival(PFS)did not significantly differ between groups.Leukopenia risk was significantly lower in the GS group than the GnP group(14.9%vs.28.1%,P=0.049).Conclusions:As first-line chemotherapy for advanced PDAC,the GS regimen led to a significantly longer OS than the GnP regimen.The PFS,ORR,and incidence of severe adverse events were comparable between the GS and GnP groups.
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.
