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Leukemia,an effective model for chemical biology and target therapy

Acta Pharmacologica Sinica 2007年第9期28卷 1316-1324页

作者： Guo-qiang CHEN~(2,3,4),Li-shun WANG~2,Ying-li WU~2,Yun YU~2~2 Department of Pathophysiology,Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education,Shanghai Jiao TongUniversity School of Medicine(SJTU-SM,formerly Shanghai Second Medical University),Shanghai 200025,China,~3 Institute of HealthScience,SJTU-SM/Shanghai Institutes for Biological Sciences,Shanghai 200025,China Department of Pathophysiology Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education Shanghai Jiao Tong University School of Medicine (SJTU-SM formerly Shanghai Second Medical University) Shanghai China Institute of Health Science SJTU-SM/Shanghai Institutes for Biological Sciences Shanghai China

The rapid rise of chemical biology aimed at studying signaling networks for basiccellular activities using specific,active small molecules as probes has greatlyaccelerated research on pathological mechanisms and target therapy of *** research is especially important for malignant tumors such as leukemia,aheterogeneous group of hematopoietic malignancies that occurs *** use of a chemical approach combined with genetic manipulation,great progresshas been achieved over the past few decades on the biological,molecular andcytogenetic aspects of leukemia,and in its diagnosis and *** particular,discoveries of the clinical effectiveness of all-trans retinoic acid and arsenictrioxide in the treatment of acute promyelocytic leukemia and the kinase inhibitorsImatinib and Dasatinib in the treatment of chronic myelogenous leukemia not onlymake target therapy of leukemia a reality,but also push mechanisms of leukemo-genesis and leukemic cell activities *** review will outline advances inchemical biology that help our understanding of the molecular mechanisms of celldifferentiation and apoptosis induction and target therapy of leukemia.

关键词： leukemia chemical biology target therapy retinoic acid arsenic trioxide differentia tion apoptosis

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A practical strategy to subcutaneous administered in-situ gelling co-delivery system of arsenic and retinoic acid for the treatment of acute promyelocytic leukemia

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Asian Journal of Pharmaceutical Sciences 2021年第5期16卷 633-642页

作者： Xiao Liu Weiwei Yin Andy Samuel Widjaya Yueying Yang Yunhu Liu Yanyan Jiang Department of Pharmaceutics School of PharmacyFudan UniversityShanghai 201023China

arsenic trioxide(ATO) combined with all trans retinoic acid(ATRA) is the first choice for the treatment of low and medium risk acute promyelocytic leukemia(APL). Clinical studies reported that the combination of ATO and ATRA could achieve a significant curative effect. However, the retinoic acid syndrome, serious drug resistance and the short half-life in vivo which lead to frequent and large dose administration limit the application of ATRA. In addition, the preparations of arsenic are conventional injections and tablets in clinic, which has poor patients’ compliance caused by frequent long-term administration and serious side effects. In order to overcome the above limitations, a phospholipid phase separation gel(PPSG) loaded with ATO and ATRA was developed. ATO + ATRA-PPSG(AAP), as a biodegradable sustained-release delivery system, was the first achievement of co-delivery of hydrophilic ATO and lipophilic ATRA with high drug loading which is the main problem in the application of nano preparation. The prepared PPSG displayed high safety and biocompatibility. The drug in PPSG was released slowly and continuously in vivo and in vitro for up to 10 d, which could reduce the side effects caused by the fluctuation of blood drug concentration and solve the problem of the long treatment cycle and frequent administration. In vivo pharmacokinetics depicted that PPSG could improve the bioavailability, decrease the peak concentration, and prolong the t 1/2 of ATO and ATRA. Particularly, AAP significantly inhibited the tumor volume, extended the survival period of tumor-bearing mice, and promoted the differentiation of APL cells into normal cells. Therefore, ATO + ATRA-PPSG not only could co-load hydrophilic ATO and lipophilic ATRA according to the clinical dosage, but also possessed the sustained-release and long-acting treatment effect which was expected to reduce administration time and ameliorate compliance of patients. Thus, it had great potential for clinical transforma

关键词： arsenic trioxide All trans retinoic acid Phospholipid phase separation gel Sustained-release Bioavailability Compliance

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CD71-mediated liposomal arsenic-nickel complex combined with all-trans retinoic acid for the efficacy of acute promyelocytic leukemia

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Asian Journal of Pharmaceutical Sciences 2023年第4期18卷 80-95页

作者： Xiao Liu Lili Zhang Yueying Yang Weiwei Yin Yunhu Liu Chunyi Luo Ruizhe Zhang Zhiguo Long Yanyan Jiang Bing Wang Key Laboratory of Smart Drug Delivery Ministry of EducationDepartment of PharmaceuticsSchool of PharmacyFudan UniversityShanghai 201023China School of Pharmacy Shanghai University of Traditional Chinese MedicineShanghai 201203China Department of Hematology Shanghai Pudong HospitalFudan UniversityShanghai 201399China Shanghai Institute of Materia Medica Chinese Academy of SciencesShanghai 201203China

Clinically,arsenic trioxide(ATO)was applied to the treatment of acute promyelocytic leukemia(APL)as a reliable and effective frontline ***,the administration regimen of AsⅢwas limited due to its fast clearance,short therapeutic window and toxicity as *** on CD71 overexpressed on APL cells,in present study,a transferrin(Tf)-modified liposome(LP)was established firstly to encapsulate AsⅢin arsenic-nickel complex by nickel acetate gradient *** AsⅢ-loaded liposomes(AsLP)exhibited the feature of acid-sensitive release in ***-modified AsLP(Tf-AsLP)were specifically taken up by APL cells and the acidic intracellular environment triggered liposome to release AsⅢwhich stimulated reactive oxygen species level and caspase-3 ***-AsLP prolonged half-life of AsⅢin blood circulation,lowered systemic toxicity,and promoted apoptosis and induced cell differentiation at lesion site in *** that ATO combined with RA is usually applied as the first choice in clinic for APL treatment to improve the therapeutic effect,accordingly,a Tf-modified RA liposome(Tf-RALP)was designed to reduce the severe side effects of free RA and assist Tf-AsLP for better *** expected,the tumor inhibition rate of Tf-AsLP was improved significantly with the combination of Tf-RALP on subcutaneous tumor ***,APL orthotopic NOD/SCID mice model was established by 60CO irradiation and HL-60 cells intravenously *** effect of co-administration(Tf-AsLP+Tf-RALP)was also confirmed to conspicuous decrease the number of leukemia cells in the circulatory system and prolong the survival time of APL mice by promoting the APL cells’apoptosis and differentiation in peripheral blood and bone ***,Tf-modified acid-sensitive AsLP could greatly reduce the systemic toxicity of free ***,Tf-AsLP combined with Tf-RALP could achieve better ***,transferrinmodified AsⅢliposome would be a novel clinical strategy to improve patie

关键词： Transferrin arsenic trioxide Acute promyelocytic leukemia All-trans retinoic acid Liposome

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Effect of Ad-p16 Combined with CDDP or As_2O_3 on Human Bladder Cancer Cells

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Journal of Huazhong University of Science and Technology(Medical Sciences) 2003年第2期23卷 169-172页

作者：朱朝辉邢诗安林晨 Department of Urology Xiehe HospitalTongji Medical CollegeHuazhong University of Science and Technology Wuhan 430022 Central Laboratory Xiehe HospitalTongji Medical CollegeHuazhong University of Science and Technology Wuhan 430022 National Laboratory of Molecular Oncology Cancer Institute of Chinese Academy of Medical SciencesBeijing 100021

To evaluate the therapeutic efficiency of combined use of p16-expressing adenovirus and chemotherapeutic agents CDDP or As2O3 on human bladder cancer cell line EJ, the human bladder cancer cell line EJ were transfected with adenovirus-mediated p16 gene (Ad-pl6), with administration of cisplatin (CDDP) or arsenic trioxide (As2O3). The cell growth, morphological changes, cell cycle, apoptosis and molecular changes were measured using cell counting, reverse microscopy, flow cytometry, cloning formation, immunocytochemical assays and in vivo therapy experiments to evaluate the therapeutic efficacy of such combined regimen. Ad-pl6 transfer and CDDP or As2O3 administration to EJ cells could exert substantially stronger therapeutic effects than the single agent treatment. Especially in in vivo experiments, combined administration of p16 and CDDP or As2O3 induced almost tumor diminish compared to the partial tumor diminish induced by single agent. Moreover, delivery of Ad-p16, or administration of minimal-dose CDDP or As2O3or combined regimen could induce massive apoptosis of EJ cell. Cell cycle analysis demonstrated that administration of CDDP or As2O3 remarkably arrested EJ cell in G1 prior to apoptotic cell death. When treated with combined regimen, cells were arrested in G1 to a greater extent prior to apoptotic cell death. It is concluded that after introduction into EJ cell, Ad-pl6 shows enhanced therapeutic efficacy for EJ cell when used in combination with CDDP or As2O3.

关键词： cisplatin arsenic trioxide Ad-pl6 bladder cancer

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Current treatment strategy of acute promyelocytic leukemia

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Frontiers of Medicine 2011年第4期5卷 341-347页

作者： Jianqing Mi Department of Hematology Shanghai Institute of HematologyRui-Jin HospitalShanghai JiaoTong University School of MedicineShanghai 200025China

Acute promyelocytic leukemia(APL)is a unique subtype of acute myeloid leukemia(AML).The prognosis of APL has changed from the worst among the AMLs to currently the *** application of all-trans retinoic acid(ATRA)in the induction therapy of APL decreases the high mortality of newly diagnosed patients,thereby significantly improving the response *** combined with anthracycline-based chemotherapy is the current standard treatment,and for high-risk patients,high doses cytarabine have a beneficial effect on relapse *** recent years,the indications of arsenic trioxide(ATO)therapy for APL have been extended from the salvage therapy for relapse patients to the first-line treatment of de novo *** introduction of both ATRA and ATO represents great achievements in translational *** this review article,we discuss the therapeutic strategies for this disease,including the initial approaches to newly diagnosed patients,prevention,and treatment of side effects and relapse to ensure the best and timely treatment for each newly diagnosed APL patient.

关键词： acute promyelocytic leukemia all-trans retinoic acid arsenic trioxide

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SENSITIVITY OF LEUKEMIC CELL LINE HL-60 TO COMBINATION OF NEFERINE AND arsenic

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Chinese Journal of Cancer Research 2006年第3期18卷 183-187页

作者：刘革修张洹何冬梅 Institute of Hematology Jinan University Medical College Guangzhou 510632

Objective： To determine whether neferine （Nef） enhances the sensitivity of human myeloid leukemia HL-60 cells to arsenic trioxide （ATO）. Methods： Apoptosis was detected by DNA electrophoresis. Giemsa staining was used to observe the apoptotic cells under microscope. The apoptotic rates of cells were analyzed using flow cytometry. The inhibitory rates of cell growth were assayed by MTT, and the expression of P-gp was determined by flow cytometry. Results： Low doses of ATO （1.0 μmol/L） only partially inhibitory percentage of cell growth at 72 h was （9.92±3.03） % （P〉0.05, vs control）. The combination of 1.0 μmol/L ATO with 2.0 μmol/L Nef inhibited （45.27±4.93） % of cell growth, and induced apoptosis in leukemic cells more significantly than wither ATO or Nef on their own （P〈0.01）. Moreover, ATO-induced expression of P-gp in leukemic cells was inhibited significantly by Nef. Conclusion： These results indicate that Nef significantly increases sensitivity of leukemic cells to ATO, which might be associated with inhibitory expression of P-gp gene. Combined use of the two agents could be a novel and attractive strategy in leukemia treatment.

关键词： Neferine Apoptosis arsenic trioxide Leukemia

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Prospect of research and clinical application of arsenic compounds in chemotherapy for gynecological malignant tumors

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Gynecology and Obstetrics Clinical Medicine 2022年第1期2卷 23-28页

作者： Yue Dong Xiaoping Li Department of Obstetrics and Gynecology Peking University People's HospitalBeijingChina Department of Obstetrics and Gynecology Beijing Jingmei Group General HosptialBeijingChina

arsenic compounds,including various arsenic-containing compounds such as intravenous use of arsenic trioxide(ATO)and an oral tetra-arsenic tetra-sulfide(As4S4)-containing formula named the Realgar-Indigo naturalis formula(RIF).RIF,also known as Compound Huangdai Tablets,which exert anti-tumor effects through a variety of mechanisms,such as the induction of programmed cell death,induction of G1 or G2/M phase arrest,epigenetic regulation of miRNAs,and suppression of cancer stem cell *** multicenter clinical studies have shown that ATO and RIF have anti-tumorigenic effects on hematological tumors and some *** compounds also been used in the treatment of cervical cancer,endometrial cancer,ovarian cancer,especially advanced drug-resistant ovarian *** article introduces the progress of ATO in combination chemotherapy,such as ATO with paclitaxel,adriamycin,cisplatin,etc in solid tumors and gynecological malignant *** side effects associated with arsenic treatment,including cardiac disorders,skin and bone marrow suppression,*** also discussed in this *** arsenic drugs also have a good therapeutic effect,it may be an outpatient oral chemotherapy new model for RIF to treatment recurrent ovarian cancer.

关键词： Gynecological malignant tumors Chemotherapy Drug resistance arsenic trioxide Oral arsenic Traditional Chinese medicine

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Extraction of arsenic from arsenic-containing cobalt and nickel slag and preparation of arsenic-bearing compounds

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Transactions of Nonferrous Metals Society of China 2014年第6期24卷 1918-1927页

作者：余国林张盈郑诗礼邹兴王晓辉张懿北京科技大学冶金与生态工程学院北京100083 中国科学院过程工程研究所湿法冶金清洁生产技术国家工程实验室北京100190

The arsenic extraction from the arsenic-containing cobalt and nickel slag,which came from the purification process of zinc sulfate solution in a zinc smelting factory,was *** alkaline leaching method was proposed according to the mode of occurrence of arsenic in the slag and its amphoteric *** leaching experiments were conducted in the alkaline aqueous medium,with bubbling of oxygen into the solution,and the optimal conditions for leaching arsenic were *** results showed that the extraction rate of arsenic was maximized at 99.10%under the optimal conditions of temperature 140 ℃,NaOH concentration 150 g/L,oxygen partial pressure 0.5 MPa,and a liquid-to-solid ratio 5：*** on the solubilities of As2O5,ZnO and PbO in NaOH solution at 25 ℃,a method for the separation of As in the form of sodium arsenate salt from the arsenic-rich leachate via cooling crystallization was established,and the reaction medium could be fully *** crystallization rate was confirmed to reach 88.9%（calculated on the basis of Na3AsO4） upon a direct cooling of the hot leachate down to room *** the basis of redox potentials,the sodium arsenate solution could be further reduced by sulfur dioxide（SO2） gas to arsenite,at a reduction yield of 92%under the suitable *** trioxide with regular octahedron shape could be prepared successfully from the reduced solution,and further recycled to the purification process to purify the zinc sulfate ***,sodium arsenite solution obtained after the reduction of arsenate could be directly used to purify the zinc sulfate ***,the technical scheme of alkaline leaching with pressured oxygen,cooling crystallization,arsenate reduction by SO2 gas,and arsenic trioxide preparation,provides an attractive approach to realize the resource utilization of arsenic-containing cobalt and nickel slag.

关键词： arsenic-containing cobalt and nickel slag alkaline leaching cooling crystallization sodium arsenate arsenic trioxide

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Reduction and deposition of arsenic in copper electrolyte

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Transactions of Nonferrous Metals Society of China 2011年第12期21卷 2772-2777页

作者：周文科彭映林郑雅杰马玉天崔涛中南大学冶金科学与工程学院长沙410083 金川集团有限公司精炼厂金昌737100

The influences of temperature, H2SO4 concentration, CuSO4 concentration, reaction time and SO2 flow rate on the reduction of arsenic（V） with SO2 were studied and the deposition behavior of arsenic （III） under the effect of concentration and co-crystallization was investigated in copper electrolyte. The results indicate that reduction rate of arsenic （V） decreases with increasing temperature and H2SO4 concentration, but increases with increasing SO2 flow rate and reaction time, and it can reach 92% under appropriate conditions that reaction temperature is 65 °C, H2SO4 concentration is 203 g/L, CuSO4 concentration is 80 g/L, reaction time is 2 h and SO2 gas flow rate is 200 mL/min. To remove arsenic in the copper electrolyte, arsenic （V） is reduced to trivalence under the appropriate conditions, the copper electrolyte is concentrated till H2SO4 concentration reaches 645 g/L, and then the removal rates of As, Cu, Sb and Bi reach 83.9%, 87.1%, 21.0% and 84.7%. The XRD analysis shows that crystallized product obtained contains As2O3 and CuSO4·5H2O.

关键词： copper electrolyte arsenic (V) reduction sulfur dioxide concentration arsenic trioxide

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Separation and recovery of Cu and As during purification of copper electrolyte

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Transactions of Nonferrous Metals Society of China 2012年第9期22卷 2268-2273页

作者：彭映林郑雅杰周文科陈文汨中南大学冶金科学与工程学院长沙410083

Cu, As, Sb and Bi in copper electrolyte could be efficiently removed by reducing with SO2 followed by evaporative crystallization. As2O3 and CuSO4·5H2O were obtained after crystallized product was treated by dissolution, oxidation, neutralization, sedimentation, filtration and evaporative crystallization. The removal rates of Cu, As, Sb and Bi are 87.1%, 83.9%, 21.0% and 84.7%, respectively, when As （Ⅴ） in copper electrolyte is fully reduced to As （Ⅲ） by SO2, and the H2SO4 in concentrated copper electrolyte is 645 g/L. The removal rate of As is 92.81% when 65 g crystallized product is dissolved in 200 mL water at 30 ℃. The CuSO4·5H2O content is 98.8% when the filtrate is purified under the conditions that n（Fe）：n（As） is 1.2, the dosage of H2O2 is 19 times the stoichiometric needed, temperature is 45 ℃, time is 40 min, pH is 3.7, and then is evaporation crystallized.

关键词： copper electrolyte sulfur dioxide purification copper sulfate arsenic trioxide

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