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Oncogenic β-catenin-driven liver cancer is susceptible to methotrexate-mediated disruption of nucleotide synthesis

Chinese Medical Journal 2024年第2期137卷 181-189页

作者： Fangming Liu Yuting Wu Baohui Zhang Shuhui Yang Kezhuo Shang Jie Li Pengju Zhang Weiwei Deng Linlin Chen Liang Zheng Xiaochen Gai Hongbing Zhang Department of Physiology State Key Laboratory of Common Mechanism Research for Major DiseasesHaihe Laboratory of Cell EcosystemInstitute of Basic Medical Sciences and School of Basic MedicineChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing 100005China Department of Physiology Institute of Basic Medical Sciences and School of Basic MedicineGraduate School of Peking Union Medical CollegeChinese Academy of Medical SciencesBeijing100005China Department of Physiology School of Life ScienceChina Medical UniversityShenyangLiaoning 110122China School of Life Sciences Westlake UniversityHangzhouZhejiang 310024China Key Laboratory of Pediatric Hematology and Oncology Ministry of HealthInstitute of Pediatric Translational MedicineShanghai Children’s Medical CenterShanghai Jiao Tong School of MedicineShanghai 200127China

Background:Liver cancer is largely resistant to chemotherapy.This study aimed to identify the effective chemotherapeutics forβ-catenin-activated liver cancer which is caused by gain-of-function mutation of catenin beta 1(CTNNB1),the most frequently altered proto-oncogene in hepatic neoplasms.Methods:Constitutiveβ-catenin-activated mouse embryonic fibroblasts(MEFs)were established by deleting exon 3(β-catenin^(Δ(ex3)/+)),the most common mutation site in CTNNB1 gene.A screening of 12 widely used chemotherapy drugs was conducted for the ones that selectively inhibitedβ-catenin^(Δ(ex3)/+)but not for wild-type MEFs.Untargeted metabolomics was carried out to examine the alterations of metabolites in nucleotide synthesis.The efficacy and selectivity of methotrexate(MTX)onβ-catenin-activated human liver cancer cells were determined in vitro.Immuno-deficient nude mice subcutaneously inoculated withβ-catenin wild-type or mutant liver cancer cells and hepatitis B virus(HBV);β-catenin^(lox(ex3)/+)mice were used,respectively,to evaluate the efficacy of MTX in the treatment ofβ-catenin mutant liver cancer.Results:MTX was identified and validated as a preferential agent against the proliferation and tumor formation ofβ-catenin-activated cells.Boosted nucleotide synthesis was the major metabolic aberration inβ-catenin-active cells,and this alteration was also the target of MTX.Moreover,MTX abrogated hepatocarcinogenesis of HBV;β-catenin^(lox(ex3)/+)mice,which stimulated concurrent Ctnnb1-activated mutation and HBV infection in liver cancer.Conclusion:MTX is a promising chemotherapeutic agent forβ-catenin hyperactive liver cancer.Since repurposing MTX has the advantages of lower risk,shorter timelines,and less investment in drug discovery and development,a clinical trial is warranted to test its efficacy in the treatment ofβ-catenin mutant liver cancer.

关键词： Liver cancer β-catenin methotrexate Nucleotide synthesis Chemotherapy

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methotrexate combined with methylprednisolone for the recovery of motor function and differential gene expression in rats with spinal cord injury

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Neural Regeneration Research 2017年第9期12卷 1507-1518页

作者： Jian-tao Liu Si Zhang Bing Gu Hua-nan Li Shuo-yu Wang Shui-yin Zhang Jiangxi Key Laboratory of Bioprocess Engineering Jiangxi Science & Technology Normal University Department of Spine Surgery Affiliated Hospital of Jiangxi University of Traditional Chinese Medicine

Methylprednisolone is a commonly used drug for the treatment of spinal cord injury, but high doses of methylprednisolone can increase the incidence of infectious diseases. methotrexate has anti-inflammatory activity and immunosuppressive effects, and can reduce in- flammation after spinal cord injury. To analyze gene expression changes and the molecular mechanism of methotrexate combined with methylprednisolone in the treatment of spinal cord injury, a rat model of spinal cord contusion was prepared using the PinPointTM preci- sion cortical impactor technique. Rats were injected with methylprednisolone 30 mg/kg 30 minutes after injury, and then subcutaneously injected with 0.3 mg/kg methotrexate 1 day after injury, once a day, for 2 weeks. TreadScan gait analysis found that at 4 and 8 weeks after injury, methotrexate combined with methylprednisolone significantly improved hind limb swing time, stride time, minimum longitudinal deviation, instant speed, footprint area and regularity index. Solexa high-throughput sequencing was used to analyze differential gene ex- pression. Compared with methylprednisolone alone, differential expression of 316 genes was detected in injured spinal cord treated with methotrexate and methylprednisolone. The 275 up-regulated genes were mainly related to nerve recovery, anti-oxidative, anti-inflammatory and anti-apoptotic functions, while 41 down-regulated genes were mainly related to proinflammatory and pro-apoptotic functions. These results indicate that methotrexate combined with methylprednisolone exhibited better effects on inhibiting the activity of inflammatory cytokines and enhancing antioxidant and anti-apoptotic effects and thereby produced stronger neuroprotective effects than methotrexate alone. The 316 differentially expressed genes play an important role in the above processes.

关键词： nerve regeneration spinal cord injury methotrexate methylprednisolone gait gene expression profile inflammation oxidative stress apoptosis nerve repair Solexa gene sequencing secondary lesion neural regeneration

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MicroRNA–disease Network Analysis Repurposes methotrexate for the Treatment of Abdominal Aortic Aneurysm in Mice

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Genomics, Proteomics & Bioinformatics 2023年第5期21卷 1030-1042页

作者： Yicong Shen Yuanxu Gao Jiangcheng Shi Zhou Huang Rongbo Dai Yi Fu Yuan Zhou Wei Kong Qinghua Cui Department of Physiology and Pathophysiology School of Basic Medical SciencesState Key Laboratory of Vascular Homeostasis and RemodelingPeking UniversityBeijing 100191China State Key Laboratory of Lunar and Planetary Sciences Macao University of Science and TechnologyMacao Special Administrative Region 999078China Department of Biomedical Informatics Center for Noncoding RNA MedicineSchool of Basic Medical SciencesPeking UniversityBeijing 100191China

Abdominal aortic aneurysm(AAA)is a permanent dilatation of the abdominal aorta and is highly lethal.The main purpose of the current study is to search for noninvasive medical therapies for AAA,for which there is currently no effective drug therapy.Network medicine represents a cuttingedge technology,as analysis and modeling of disease networks can provide critical clues regarding the etiology of specific diseases and therapeutics that may be effective.Here,we proposed a novel algorithm to quantify disease relations based on a large accumulated microRNA–disease association dataset and then built a disease network covering 15 disease classes and 304 diseases.Analysis revealed some patterns for these diseases.For instance,diseases tended to be clustered and coherent in the network.Surprisingly,we found that AAA showed the strongest similarity with rheumatoid arthritis and systemic lupus erythematosus,both of which are autoimmune diseases,suggesting that AAA could be one type of autoimmune diseases in etiology.Based on this observation,we further hypothesized that drugs for autoimmune diseases could be repurposed for the prevention and therapy of AAA.Finally,animal experiments confirmed that methotrexate,a drug for autoimmune diseases,was able to alleviate the formation and development of AAA.

关键词： Abdominal aortic aneurysm Network medicine MicroRNA-derived disease network Autoimmune disease methotrexate

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World Journal of Clinical Cases 2019年第21期7卷 3553-3561页

作者： Takeshi Mizusawa Kenya Kamimura Hiroki Sato Takeshi Suda Hiroyuki Fukunari Go Hasegawa Osamu Shibata Shinichi Morita Akira Sakamaki Junji Yokoyama Yu Saito Yoshihisa Hori Yuduru Maruyama Fumitoshi Yoshimine Takahiro Hoshi Shinichi Morita Tsutomu Kanefuji Masaaki Kobayashi Shuji Terai Department of Internal Medicine Niigata Prefectural Tokamachi HospitalTokamachiNiigata 948-0065Japan Division of Gastroenterology and Hepatology Graduate School of Medical and Dental SciencesNiigata UniversityNiigata 951-8122Japan Department of Gastroenterology and Hepatology Uonuma Institute of Community Medicine Niigata University HospitalMinami UonumaNiigata 949-7302Japan Department of Surgery Niigata Prefectural Tokamachi HospitalTokamachiNiigata 948-0065Japan Department of Pathology Uonuma Institute of Community Medicine Niigata University HospitalMinami UonumaNiigata 949-7302Japan Department of Internal Medicine Tokamachi Central ClinicTokamachiNiigata 948-0065Japan

BACKGROUND Immunosuppression is effective in treating a number of diseases,but adverse effects such as bone marrow suppression,infection,and oncogenesis are of concern.methotrexate is a key immunosuppressant used to treat rheumatoid arthritis.Although it is effective for many patients,various side effects have been reported,one of the most serious being methotrexate-related lymphoproliferative disorder.While this may occur in various organs,liver involvement is rare.Information on these liver lesions,including clinical characteristics,course,and imaging studies,has not been summarized to date.CASE SUMMARY We present a case of 70-year-old woman presented with a 2-wk history of fever and abdominal pain.She had had rheumatoid arthritis for 5 years and was being treated with medication including methotrexate.Contrast-enhanced computed tomography revealed multiple low density tumors in the liver and the histological analyses showed significant proliferation of lymphocytes in masses that were positive on immunohistochemical staining for CD3,CD4,CD8,and CD79a but negative for CD20 and CD56.Staining for Epstein-Barr virus-encoded RNA was negative.And based on these findings,the liver tumors were diagnosed as methotrexate-related lymphoproliferative disorders.A timedependent disappearance of the liver tumors after stopping methotrexate supported the diagnoses.CONCLUSION The information obtained from our case and a review of 9 additional cases reported thus far assist physicians who may face the challenge of diagnosing and managing this disorder.

关键词： Arthritis Rheumatoid methotrexate Malignant lymphoma Case report

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Dose-individualization Efficiently Maintains Sufficient Exposure to methotrexate without Additional Toxicity in High-dose methotrexate Regimens for Pediatric Acute Lymphoblastic Leukemia

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Current Medical Science 2022年第4期42卷 769-777页

作者： Ya-qing SHEN Zhu-jun WANG Xiao-yan WU Kun LI Zhong-jian WANG Wen-fu XU Fen ZHOU Run-ming JIN Department of Pediatrics Union HospitalTongji Medical CollegeHuazhong University of Science and TechnologyWuhan 430022China

Objective:methotrexate(MTX)can be safely administered to most patients but may cause severe toxicity in others.This study aimed to summarize the characteristics of high-dose methotrexate(HD-MTX)chemotherapy and to evaluate whether the modified dose-adjustment program was able to improve the maintenance of sufficient MTX exposure levels while minimizing toxicities.Methods:We evaluated 1172 cycles of high-dose MTX chemotherapy from 294 patients who were treated according to the CCCG-ALL-2015 protocol(clinical trial number:ChiCTR-IPR-14005706)and analyzed the data of actual MTX dosage,MTX concentration,toxicity,and prognosis.We compared data between the dose-adjustment Program 1(fixed 20%reduction in dose)and the dose-adjustment Program 2(dose-individualization based on reassessment of the creatine clearance rate and the MTX concentration-monitoring point at 16 h),which were applied if the MTX clearance was delayed in the previous cycle.Results:The patients who used Program 2 had higher actual MTX infusion doses and infusion rates and were able to better maintain the MTX concentration at 44 h at the established target value than those on Program 1(P<0.001).No significant differences in toxicities were found between these two programs except that abnormal serum potassium levels and prolonged myelosuppression in intermediate-risk/high-risk patients were more frequently observed in patients using Program 2(P<0.001).No significant correlations were observed between the MTX dose,dose-adjustment programs,or MTX concentrations and relapse-free survival.Conclusion:Adjusting the MTX dose using Program 2 is more efficient for maintaining sufficient MTX exposure without significantly increasing the toxicity.

关键词： methotrexate high-dose methotrexate individualizing methotrexate dose toxicity acute lymphoblastic leukemia prognosis

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Effects of genetic polymorphisms on methotrexate levels and toxicity in Chinese patients with acute lymphoblastic leukemia

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Blood Science 2023年第1期5卷 32-38页

作者： Qishan Hao Yang Song Qiuyun Fang Yani Lin Long Chen Xiaodan Wang Ping Zhang Zhe Wang Xiaoyuan Gong Kaiqi Liu Qinghua Li Zheng Tian Min Wang Jianxiang Wang Yingchang Mi State Key Laboratory of Experimental Hematology National Clinical Research Center for Blood DiseasesHaihe Laboratory of Cell EcosystemInstitute of Hematology&Blood Diseases HospitalChinese Academy of Medical Sciences&Peking Union Medical CollegeTianjinChina SINO-US Diagnostics Lab TianjinChina

methotrexate(MTX)has an antitumor effect when used for the treatment of acute lymphoblastic leukemia(ALL).This study aims at evaluating the associations between 14 polymorphisms of six genes involved in MTX metabolism with serum MTX concentration and toxicity accompanying high-dose MTX.Polymorphisms in 183 Chinese patients with ALL were analyzed using TaqMan single nucleotide polymorphism genotyping assay.The serum MTX concentration was determined using homogeneous enzyme immunoassay.MTX-related toxicities were also evaluated.Renal toxicity was significantly associated with higher serum MTX concentrations at 24,48,and 72 hours,and MTX elimination delay(P=0.001,P<0.001,P<0.001,and P<0.001,respectively),whereas SLCO1B1 rs4149056 was associated with serum MTX concentrations at 48 and 72 hours,and MTX elimination delay in candidate polymorphisms(P=0.014,P=0.019,and P=0.007,respectively).SLC19A1 rs2838958 and rs3788200 were associated with serum MTX concentrations at 24 hours(P=0.016,P=0.043,respectively).MTRR rs1801394 was associated with serum MTX concentrations at 72 hours(P=0.045).Neutropenia was related to SLC19A1 rs4149056(odds ratio[OR]:3.172,95%confidence interval[CI]:1.310–7.681,P=0.011).Hepatotoxicity was associated with ABCC2 rs2273697(OR:3.494,95%CI:1.236–9.873,P=0.018)and MTRR rs1801394(OR:0.231,95%CI:0.084–0.632,P=0.004).Polymorphisms of SLCO1B1,SLC19A1,ABCC2,and MTRR genes help predict higher risk of increased MTX levels or MTX-related toxicities in adult ALL patients.

关键词： Acute lymphoblastic leukemia Concentration methotrexate Polymorphism Toxicity

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methotrexate for chronic non-necrotizing anterior scleritis in Chinese patients

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International Journal of Ophthalmology(English edition) 2022年第8期15卷 1261-1265页

作者： Jun-Yan Xiao An-Yi Liang Fei Gao Chan Zhao Mei-Fen Zhang Department of Ophthalmology Peking Union Medical College HospitalChinese Academy of Medical Sciences&Peking Union Medical CollegeBeijing 100730China Department of Ophthalmology Guangdong Provincial People’s HospitalGuangdong Academy of Medical SciencesGuangdong Eye InstituteGuangzhou 510080Guangdong ProvinceChina Key Laboratory of Ocular Fundus Diseases Chinese Academy of Medical Sciences&Peking Union Medical CollegeBeijing 100730China

AIM:To evaluate the effectiveness and corticosteroidsparing capabilities of methotrexate(MTX)in the treatment of chronic non-necrotizing anterior scleritis in Chinese patients.METHODS:A retrospective chart review of all patients with active anterior scleritis between January 2015 and June 2019 was conducted.All patients received 10 to 15 mg/wk MTX orally,and corticosteroids(10 to 40 mg/d prednisolone or equivalent methylprednisolone)with slow tapering.Topical corticosteroid eye drops(1%prednisolone actate,0.1%dexmathosone or 0.1%fluoromethalone)were applied to control comorbid anterior uveitis at presentation or during follow up.The main outcomes were inflammation control and corticosteroid-sparing success,and secondary outcomes were reduction of immunosuppression load and best-corrected visual acuity(BCVA).RESULTS:Thirty-two eyes(22 patients)were included.The proportion of patients who achieved corticosteroidsparing success was 50.0%at 3mo and 77.3%at 12mo[8(36.4%)patients discontinued corticosteroid].The proportion of eyes that achieved inflammation control was 59.4%at 3mo and 78.1%at 12mo.The immunosuppression load was 5.14±0.87 at presentation and 2.76±2.34 at 12mo(P<0.01).BCVA maintained unchanged or improved in 29(90.6%)of all affected eyes.One patient discontinued MTX treatment because of an abnormal liver function test,and no other serious adverse effects were observed.CONCLUSION:According to this pilot study,low dose MTX appear to be a well-tolerated and effective treatment for chronic non-necrotizing anterior scleritis patients in the Chinese population.

关键词： methotrexate non-necrotizing anterior scleritis pharmacotherapy corticosteroid-sparing Chinese population

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Salvage treatment in IDH1 mutated acute lymphoblastic leukemia with venetoclax plus methotrexate and pegaspargase:A case report

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Genes & Diseases 2023年第6期10卷 2215-2217页

作者： Dan Li Shuqi Zhao Liping Mao Jie Jin Jinghan Wang Department of Hematology Shaoxing People's HospitalShaoxingZhejiang 312000China Department of Hematology The First Affiliated HospitalZhejiang University School of MedicineHangzhouZhejiang 310003China

Acute myeloid leukemia(AML)and acute lymphoblastic leukemia(ALL)are distinct subtypes of acute leukemia with respect to clinical and genetic features.Recently,ALLs were reported to share similar genes like IDH1 mutations to AMLs.1 Specifically,mutated IDH1(5%-15%)frequently occurs in AML and scarcely(1.9%)in ALL.1 Notably,IDH1 along with SRSF2mutation often exists in secondaryAMLpatients and confers a poor prognosis.Recently,venetoclax(VEN)has been demonstrated extremely effective in combination with a hypomethylating agent or chemotherapy for IDH1 mutated AML patients.However,whether VEN combining chemotherapy is effective among ALL patients with similar genetic features to AML remains unclear.Here,we successfully rescued a relapsed ALL case with IDH1 mutation by VEN plus methotrexate and pegaspargase based on their antimetabolic pathways.

关键词： IDH1 methotrexate chemotherapy

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Systemic combined with intravitreal methotrexate for relentless placoid chorioretinitis:A case report

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World Journal of Clinical Cases 2022年第35期10卷 13115-13121页

作者： Lan Luo Wei-Bin Chen Ming-Wei Zhao Heng Miao Department of Ophthalmology&Clinical Center of Optometry Peking University People’s HospitalBeijing 100044China Eye Diseases and Optometry Institute Peking University People's HospitalBeijing 100044China College of Optometry Peking University Health Science CenterBeijing 100191China Beijing Key Laboratory of Diagnosis and Therapy of Retinal and Choroid Diseases Peking University People's HospitalBeijing 100044China

BACKGROUND We describe a case of relentless placoid chorioretinitis(RPC)that progressed despite administration of peribulbar and systemic corticosteroids,and was resolved by systemic combined with intravitreal methotrexate.CASE SUMMARY A 16-year-old male reported painless blurred vision and a temporal scotoma in his right eye for one week.Due to widespread distribution and continuous enlargement,multimodal imaging of the lesions led to the diagnosis of RPC.Lesions in the right eye extended despite peribulbar injection of triamcinolone acetonide,but the progression was immediately terminated by a single dose of intravitreal methotrexate.A new fresh lesion occurred in the contralateral eye despite systemic prednisolone but was resolved by oral methotrexate.CONCLUSION Systemic immunosuppressants should be given upon RPC diagnosis.Intravitreal methotrexate immediately halted progression and may be considered for sightthreatening cases as part of the initial therapy.

关键词： Immunosuppression Intravitreal methotrexate Relentless placoid chorioretinitis Systemic Case report

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Analytical methodologies for determination of methotrexate and its metabolites in pharmaceutical,biological and environmental samples

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Journal of Pharmaceutical Analysis 2019年第6期9卷 373-391页

作者： Forough Karami Sara Ranjbar Younes Ghasemi Manica Negahdaripour Pharmaceutical Sciences Research Center Shiraz University of Medical SciencesShirazIran Central Research Laboratory School of MedicineShiraz University of Medical SciencesShirazIran Chemistry Department Yasouj UniversityYasoujIran Department of Pharmaceutical Biotechnology School of PharmacyShiraz University of Medical SciencesShirazIran

methotrexate(MTX)is a folate antagonist drug used for several diseases,such as cancers,various malignancies,rheumatoid arthritis(RA)and inflammatory bowel disease.Due to its structural features,including the presence of two carboxylic acid groups and its low native fluorescence,there are some challenges to develop analytical methods for its determination.MTX is metabolized to 7-hydroxymethotrexate(7-OH-MTX),2,4-diamino-N10-methylpteroic acid(DAMPA),and the active MTX polyglutamates(MTXPGs)in the liver,intestine,and red blood cells(RBCs),respectively.Additionally,the drug has a narrow therapeutic range;hence,its therapeutic drug monitoring(TDM)is necessary to regulate the pharmacokinetics of the drug and to decrease the risk of toxicity.Due to environmental toxicity of MTX;its sensitive,fast and low cost determination in workplace environments is of great interest.A large number of methodologies including high performance liquid chromatography equipped with UVevisible,fluorescence,or electrochemical detection,liquid chromatography-mass spectroscopy,capillary electrophoresis,UVevisible spectrophotometry,and electrochemical methods have been developed for the quantitation of MTX and its metabolites in pharmaceutical,biological,and environmental samples.This paper will attempt to review several published methodologies and the instrumental conditions,which have been applied to measure MTX and its metabolites within the last decade.

关键词： methotrexate Antifolate Anticancer Quantification High performance liquid chromatography

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