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| 1 | Inhibition of Mcl-1 enhances cell death induced by the Bcl-2-selective inhibitor ABT-199 in acute myeloid leukemia cells显示文摘Acute myeloid leukemia(AML)is a serious disease.The 5-year survival rates remain frustratingly low(65%for children and 26%for adults).Resistance to frontline chemotherapy(usually cytarabine)often develops;therefore a new treatment modality is needed.Bcl-2 family proteins play an important role in balancing cell survival and apoptosis.The antiapoptotic Bcl-2 family proteins have been found to be dysregulated in AML.ABT-199,a BH3 mimetic,was developed to target antiapoptotic protein Bcl-2.Although ABT-199 has demonstrated promising results,resistance occurs.Previous studies in AML show that ABT-199 alone decreases the association of proapoptotic protein Bim with Bcl-2,but this is compensated by increased association of Bim with prosurvival protein Mcl-1,stabilizing Mcl-1,resulting in resistance to ABT-199.In this study,we investigated the antileukemic activity of the Mcl-1-selective inhibitor A-1210477 in combination with ABT-199 in AML cells.We found that A-1210477 synergistically induced apoptosis with ABT-199 in AML cell lines and primary patient samples.The synergistic induction of apoptosis was decreased upon Bak,Bax and Bim knockdown.While A-1210477 treatment alone also increased Mcl-1 protein levels,combination with ABT-199 reduced binding of Bim to Mcl-1.Our results demonstrate that sequestration of Bim by Mcl-1,a mechanism of ABT-199 resistance,can be abrogated by combined treatment with the Mcl-1 inhibitor A-1201477. | Daniel A Luedtke Xiaojia Niu Yihang Pan Jianyun Zhao Shuang Liu Holly Edwards Kang Chen Hai Lin Jeffrey W Taub Yubin Ge | 2017 | Signal Transduction and Targeted Therapy2017，2，1： | 11 |
| 2 | Signaling pathways and therapeutic interventions in gastric cancer显示文摘Gastric cancer(GC)ranks fifth in global cancer diagnosis and fourth in cancer-related death.Despite tremendous progress in diagnosis and therapeutic strategies and significant improvements in patient survival,the low malignancy stage is relatively asymptomatic and many GC cases are diagnosed at advanced stages,which leads to unsatisfactory prognosis and high recurrence rates.With the recent advances in genome analysis,biomarkers have been identified that have clinical importance for GC diagnosis,treatment,and prognosis.Modern molecular classifications have uncovered the vital roles that signaling pathways,including EGFR/HER2,p53,PI3K,immune checkpoint pathways,and cell adhesion signaling molecules,play in GC tumorigenesis,progression,metastasis,and therapeutic responsiveness.These biomarkers and molecular classifications open the way for more precise diagnoses and treatments for GC patients.Nevertheless,the relative significance,temporal activation,interaction with GC risk factors,and crosstalk between these signaling pathways in GC are not well understood.Here,we review the regulatory roles of signaling pathways in GC potential biomarkers,and therapeutic targets with an emphasis on recent discoveries.Current therapies,including signaling-based and immunotherapies exploited in the past decade,and the development of treatment for GC,particularly the challenges in developing precision medications,are discussed.These advances provide a direction for the integration of clinical,molecular,and genomic profiles to improve GC diagnosis and treatments. | Zi-Ning Lei Qiu-Xu Teng Qin Tian Wei Chen Yuhao Xie Kaiming Wu Qianlin Zeng Leli Zeng Yihang Pan Zhe-Sheng Chen Yulong He | 2022 | Signal Transduction and Targeted Therapy2022，7，11： | 4 |
| 3 | Synergistic effects of autophagy/mitophagy inhibitors and magnolol promote apoptosis and antitumor efficacy显示文摘Mitochondria as a signaling platform play crucial roles in deciding cell fate.Many classic anticancer agents are known to trigger cell death through induction of mitochondrial damage.Mitophagy,one selective autophagy,is the key mitochondrial quality control that effectively removes damaged mitochondria.However,the precise roles of mitophagy in tumorigenesis and anticancer agent treatment remain largely unclear.Here,we examined the functional implication of mitophagy in the anticancer properties of magnolol,a natural product isolated from herbal Magnolia officinalis.First,we found that magnolol induces mitochondrial depolarization,causes excessive mitochondrial fragmentation,and increases mitochondrial reactive oxygen species(mtROS).Second,magnolol induces PTEN-induced putative kinase protein 1(PINK1)-Parkin-mediated mitophagy through regulating two positive feedforward amplification loops.Third,magnolol triggers cancer cell death and inhibits neuroblastoma tumor growth via the intrinsic apoptosis pathway.Moreover,magnolol prolongs the survival time of tumor-bearing mice.Finally,inhibition of mitophagy by PINK1/Parkin knockdown or using inhibitors targeting different autophagy/mitophagy stages significantly promotes magnolol-induced cell death and enhances magnolol's anticancer efficacy,both in vitro and in vivo.Altogether,our study demonstrates that magnolol can induce autophagy/mitophagy and apoptosis,whereas blockage of autophagy/mitophagy remarkably enhances the anticancer efficacy of magnolol,suggesting that targeting mitophagy may be a promising strategy to overcome chemoresistance and improve anticancer therapy. | Yancheng Tang Liming Wang Tao Yi Jun Xu Jigang Wang Jiang-Jiang Qin Qilei Chen Ka-Man Yip Yihang Pan Peng Hong Yingying Lu Han-Ming Shen Hu-Biao Chen | 2021 | Acta Pharmaceutica Sinica B2021，11，12： | 2 |
| 4 | Modulating the function of ABCB1: in vitro and in vivo characterization of sitravatinib, a tyrosine kinase inhibitor显示文摘Background:Overexpression of ATP-binding cassette(ABC)transporter is a major contributor to multidrug resistance(MDR),in which cancer cells acquire resistance to a wide spectrum of chemotherapeutic drugs.In this work,we evaluated the sensitizing effect of sitravatinib,a broad-spectrum tyrosine kinase inhibitor(TKI),on ATP-binding cassette subfamily B member 1(ABCB1)-and ATP-binding cassette subfamily C member 10(ABCC10)-mediated MDR.Methods:MTT assay was conducted to examine cytotoxicity and evaluate the sensitizing effect of sitravatinib at non-toxic concentrations.Tritium-labeled paclitaxel transportation,Western blotting,immunofluorescence analysis,and ATPase assay were carried out to elucidate the mechanism of sitravatinib-induced chemosensitization.The in vitro findings were translated into preclinical evaluation with the establishment of xenograft models.Results:Sitravatinib considerably reversed MDR mediated by ABCB1 and partially antagonized ABCC10-mediated MDR.Our in silico docking simulation analysis indicated that sitravatinib strongly and stably bound to the transmembrane domain of ABCB1 human-mouse chimeric model.Furthermore,sitravatinib inhibited hydrolysis of ATP and synchronously decreased the efflux function of ABCB1.Thus,sitravatinib could considerably enhance the intracellular concentration of anticancer drugs.Interestingly,no significant alterations of both expression level and localization of ABCB1 were observed.More importantly,sitravatinib could remarkably restore the antitumor activity of vincristine in ABCB1-mediated xenograft model without observable toxic effect.Conclusions:The findings in this study suggest that the combination of sitrvatinib and substrate antineoplastic drugs of ABCB1 could attenuate the MDR mediated by the overexpression of ABCB1. | Yuqi Yang Ning Ji Chao-Yun Cai Jing-Quan Wang Zi-Ning Lei Qiu-Xu Teng Zhuo-Xun Wu Qingbin Cui Yihang Pan Zhe-Sheng Chen | 2020 | Cancer Communications2020，40，7： | 2 |
| 5 | Outcomes of Self-Expanding Transcatheter Pulmonary Valves:Extended Follow-Up of a Prospective Trial显示文摘Background:The Venus-P valve was the first self-expanding valve used world-wide for transcatheter pulmonary valve replacement(TPVR)in patients with severe pulmonary regurgitation(PR).We intended to report the extended follow-up results from the prospective trial(No.NCT02590679).Methods:A total of 38 patients with severe PR(mean age 24.2±13.2)were included.Follow-up data were obtained after implanted at 1,6,and 12 months and yearly after.The frame geometry was assessed on post-implant computer tomography(CT)scanning by calculating the non-circularity[circularity ratio(minimum diameter/maximum diameter)<0.9]and under-expansion[expansion ratio(derived external valve area/nominal external valve area)<0.9).Adverse events(all-cause mortality,reintervention,valve dysfunction,stent fracture and endocarditis)were recorded.Results:All valves were implanted successfully with normal function at discharge.Geometric CT analysis showed underexpanded valve was detected in 22 patients(63%)and non-circular valve was seen in 16 patients(46%).During a median follow-up of 4.8 years(range 0.3-8.1),there were 1 death and 1 surgical explant,both resulting from endocarditis.Five-year freedom from valve dysfunction and stent fracture were 84.8%(95%CI 74.8-94.7)and 83.5%(95%CI 73.8-93.2).Endocarditis occurred in 3 patients at a median time of 7 months.Stent fracture was more common in patients with non-circularity stents.Conclusion:TPVR using Venus-P valve is associated with favorable outcomes at 5 years.Non-circular shapes in the valve level may have a higher risk of stent fracture. | Jingnan Zhang Junyi Wan Yihang Li Yu Han Jiahua Pan Fang Fang Shiliang Jiang Xiangbin Pan Gejun Zhang | 2023 | Congenital Heart Disease2023，18，2： | 0 |
| 6 | Gli1 promotes epithelial-mesenchymal transition and metastasis of non-small cell lung carcinoma by regulating snail transcriptional activity and stability显示文摘Metastasis is crucial for the mortality of non-small cell lung carcinoma(NSCLC) patients.The epithelial-mesenchymal transition(EMT) plays a critical role in regulating tumor metastasis.Glioma-associated oncogene 1(Gli1) is aberrantly active in a series of tumor tissues. However, the molecular regulatory relationships between Gli1 and NSCLC metastasis have not yet been identified. Herein,we reported Gli1 promoted NSCLC metastasis. High Gli1 expression was associated with poor survival of NSCLC patients. Ectopic expression of Gli1 in low metastatic A549 and NCI-H460 cells enhanced their migration, invasion abilities and facilitated EMT process, whereas knock-down of Gli1 in high metastatic NCI-H1299 and NCI-H1703 cells showed an opposite effect. Notably, Gli1 overexpression accelerated the lung and liver metastasis of NSCLC in the intravenously injected metastasis model. Further research showed that Gli1 positively regulated Snail expression by binding to its promoter and enhancing its protein stability, thereby facilitating the migration, invasion and EMT of NSCLC. In addition, administration of GANT-61, a Gli1 inhibitor, obviously suppressed the metastasis of NSCLC. Collectively, our study reveals that Gli1 is a critical regulator for NSCLC metastasis and suggests that targeting Gli1 is a prospective therapy strategy for metastatic NSCLC. | Xueping Lei Zhan Li Yihang Zhong Songpei Li Jiacong Chen Yuanyu Ke Sha Lv Lijuan Huang Qianrong Pan Lixin Zhao Xiangyu Yang Zisheng Chen Qiudi Deng Xiyong Yu | 2022 | Acta Pharmaceutica Sinica B2022，12，10： | 0 |
| 7 | Two-dimensional coordination polymer-based nanosensor for sensitive and reliable nucleic acids detection in living cells显示文摘A reliable and sensitive strategy which can assess nucleic acid levels in living cells would be essential for fundamental research of biomedical applications. Some nanomaterial-based fluorescence biosensors recently developed for detecting nucleic acids, however, are often with expensive, complicated and timeconsuming preparation process. Here, by using a facile bottom-up synthesis method, a two-dimensional(2 D) coordination polymer(CP) nanosheet, [Cu(tz)](Htz = 1,2,4-triazole), was successfully prepared after optimizing reaction conditions. These ultrathin CP nanosheets with thickness of 4.7 ± 1.1 nm could readily form nanosensors by assembly with DNA probes, which exhibited a low limit of detection(LOD)for p53 DNA fragment as 144 pmol/L. Furthermore, by integrating [Cu(tz)] nanosheets with hybridization chain reaction(HCR) probes, mi R-21, one kind of micro RNA upregulated in many cancer cells, can be sensitively detected with a LOD of 100 pmol/L and monitored in living cells, giving consistent results with those obtained by quantitative reverse-transcription polymerase chain reaction(q RT-PCR) analysis.Thus [Cu(tz)] nanosheets, which not only possess much better nucleic acids sensing performance than bulk cystals, but also exhibit nucleic acid delivery functions, could be used as a novel nanoplatform in biomedical imaging and sensing applications. | Yuzhi Xu Yanfei Zhang Huihui Yang Wen Yin Leli Zeng Shuo Fang Si-Yang Liu Zong Dai Xiaoyong Zou Yihang Pan | 2022 | Chinese Chemical Letters2022，33，2： | 0 |
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