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Genes & Diseases 2024年第1期11卷 19-22页

作者： Zhenhai Li Wenchao Xu Feng Chen Jun Zhang Wei-Guo Zhu Guangdong Key Laboratory of Genome Instability and Human Disease Prevention Department of Biochemistry and Molecular BiologyShenzhen University School of MedicineShenzhenGuangdong 518055China School of Pharmaceutical Sciences Shenzhen University Health Science CenterShenzhenGuangdong 518055China Base for International Science and Technology Cooperation:Carson Cancer Stem Cell Vaccines R&D Center International Cancer CenterShenzhen University Health Science CenterShenzhenGuangdong 518055China Shenzhen Bay Laboratory Shenzhen University School of MedicineShenzhenGuangdong 518055China Marshall Laboratory of Biomedical Engineering Shenzhen University School of MedicineShenzhenGuangdong 518055China

etoposide is widely used for cancer chemotherapy in the clinic.However,long-term etoposide treatment can lead to adverse effects or drug resistance.To improve the situation,we evaluated the therapeutic efficiency of etoposide combined with inhibitors of bromodomain and extraterminal(BET)family proteins,which have recently emerged as novel anti-cancer targets due to their critical roles in cancer development.Firstly,we showed BRD4,one of the main targets of BET inhibitors,was involved in DNA damage response(DDR)via the homologous recombination(HR)repair pathway.

关键词： etoposide damage cancer

Protein-based nanocarriers for efficient etoposide delivery and cancer therapy

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Nano Research 2023年第8期16卷 11216-11220页

作者： Bo Wang Xiaoxiong Xu Bo Li Zheng Wei Shuang Lu Jingjing Li Kai Liu Hongjie Zhang Fan Wang Yang Yang Department of Thoracic Surgery Shanghai Pulmonary HospitalSchool of MedicineTongji UniversityShanghai 200433China Engineering Research Center of Advanced Rare Earth Materials (Ministry of Education)Department of ChemistryTsinghua UniversityBeijing 100084China State Key Laboratory of Rare Earth Resource Utilization Changchun Institute of Applied ChemistryChinese Academy of SciencesChangchun 130022China University of Science and Technology of China Hefei 230026China School of Materials Science and Engineering Tongji UniversityShanghai 201804China

etoposide,a DNA damage-inducing agent,is widely used for malignant tumors.However,insufficient solubility,poor bioavailability and adverse events limited the treatment outcomes and prognosis.To address this,we here developed a novel biosynthetic and unfolded protein nanocarrier to load and deliver etoposide.Compared with the pristine agent,the loading efficiency of the nanoformulated drug increased four times and the half-life time increased to 17.6 h with controlled release of the etoposide for 6 days.The half-maximal inhibitory concentration at 48 h was lower than that at 24 h,suggesting a long-acting anti-tumor property.Moreover,the anti-tumor performance in rat models was significantly enhanced by improving solubility and cellular internalization.Additionally,immunogenicity and adverse toxicologic effects such as kidney and liver toxicity were significantly weakened.Therefore,the assembly strategy enables etoposide with higher efficacy,bioavailability,and safety,and has great potential in the comprehensive treatment of malignant tumors.

关键词： etoposide nanocarrier solubility cellular internalization malignant tumors

Higher efficacy of oral etoposide for mobilization of peripheral blood stem cells in patients with multiple myeloma

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Blood Science 2022年第2期4卷 76-82页

作者： Wanting Qiang Hua Jiang Pei Guo Jing Lu Jin Liu Lu Li Haiyan He Xiaoxia Hu Weijun Fu Juan Du Department of Hematology Myeloma&Lymphoma CenterShanghai Changzheng HospitalNaval Medical UniversityShanghaiChina State Key Laboratory of Medical Genomics Shanghai Institute of HematologyNational Research Center for Translational MedicineShanghai Rui Jin HospitalShanghai Jiao Tong University School of MedicineShanghaiChina

This study compares the efficacy,toxicity,hematopoietic recovery,and cost of stem-cell mobilization using intermediate-dose cyclophosphamide(IDCy)plus granulocyte colony-stimulating factor(G-CSF)compared with etoposide(VP-16)plus pegylated granulocyte colony-stimulating factor(PEG-rhG-CSF)in multiple myeloma(MM)patients.Two hundred forty-four consecutive patients undergoing mobilization with IDCy(3-3.5g/m^(2))plus G-CSF(n=155)were compared with patients receiving VP-16 plus PEG-rhG-CSF(n=89),including oral etoposide(n=65)and intravenous etoposide(n=24).Compared with IDCy,VP-16 use was associated with significantly higher median peak peripheral blood CD34+cell count(8.20[range:1.84-84]×10^(6)/kg vs 4.58[range:0.1-27.9]×10^(6)/kg,P=.000),and ideal CD34+cell yield of more than 6×10^(6)/kg(56.8%vs 35.1%,P=.001),notably with a higher efficacy in oral VP-16 use compared with IDCy use(CD 34+cell counts:median peak peripheral blood 5.87 vs 4.58?106/kg and≥6×10^(6)/kg[48.4%vs 35.1%]).The median number of apheresis courses was reduced from two in the IDCy group to one in the VP-16 group(P=.000).IDCy use was associated with significantly more frequent episodes of neutropenia(70.2%vs 35.2%;P=.000),intravenous antibiotic use(13.2%vs 11.4%;P=.672),and hospitalization(P=.000).The recoveries of neutrophils and platelets after autologous stem-cell transplantation were significantly faster in the VP-16 group compared with the IDCy group(P=.000).Our data indicate robust stem-cell mobilization in MM patients with VP-16 delivered either orally or intravenously.When compared with intravenous VP-16,oral VP-16 mobilization was associated with significantly more convenient,lower average total costs,and especially decreased the risk of hospital visits and exposure.

关键词： Apheresis etoposide Intermediate-dose cyclophosphamide Multiple myeloma Oral Peripheral blood stem-cell mobilization

Effect of hydroxyurea and etoposide on transduction of human bone marrow mesenchymal stem and progenitor cell by adeno-associated virus vectors

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Acta Pharmacologica Sinica 2004年第2期25卷 70-76页

作者： Xiao-dong JU, Si-quan LOU2, Wei-guo WANG, Jian-qiang PENG3, Hua TIAN Department of Orthopaedics, Peking University Third Hospital, Beijing 100083 3Institute of Virology, Chinese Academy of Preventive Medicine, Beijing 100262, China Department of Orthopaedics Peking University Third Hospital 北京 100083 Institute of Virology Chinese Academy of Preventive Medicine 北京 100262

AIM: To study the effect of hydroxyurea and etoposide on transduction of human marrow mesenchymal and progenitor stem cells by adeno-associated virus (AAV). METHODS: Isolated human bone marrow mesenchymal stem and progenitor cells (hMSCs) were cultured in DMEM containing 10 % FBS or 5 % FBS and dexamethasone 1 μmol/L respectively. After being treated with hydroxyurea and etoposide, hMSCs were transduced by AAV-LUC. After two days luciferase activity (relative light unites per second or RLU/s) were tested, which indirectly reflected the relative transduction efficiency of different groups, and virus DNA was isolated by Hirt extraction for Southern hybridization. RESULTS: Transduction luciferase activity and transduction efficiency in cultures treated with hydroxyurea and etoposide were significantly higher than that in control cultures. Dividing cells had about 20-fold higher transduction efficiencycompared with control cells. Transduction efficiency in stationary cells was about 50 times higher than that in control cells. Southern analysis showed that hydroxyurea and etoposide enhanced second-strand DNA synthesis by rAAV. CONCLUSION: Hydroxyurea and etoposide could increase transduction efficiency of hMSCs by AAV vectors, and stationary cells were more sensitive to these drugs than dividing cells.

关键词： simian adenoviruses hydroxyurea etoposide mesoderm stem cells gene transfer techniques

etoposide Induces Mitochondria-Associated Apoptotic Cell Death in Human Gastric Carcinoma Cells

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Chemical Research in Chinese Universities 2008年第5期24卷 597-602页

作者： LI Jing-hua CHEN Yue WANG Jia-si KONG Wei JIN Ying-hua Key Laboratory for Molecular Enzymology and Engineering Ministry of Education College of Life Science School of Public Health Jilin University Changchun 130012 P R. China

Recent observations indicate that the resistance of apoptosis is an important process of tumor metastasis and metastases are the cause of 90% of human cancer death. etoposide, a semisynthetic derivative of the podophyllotoxins, is a clinically used anti-cancer reagent, but the effects of it on metastatic gastric carcinoma cells are totally unknown. In this study, etoposide induced apoptotic cell death in human gastric adenocarcinoma cell line SGC-7901, derived from metastatic lymph nodes, as evidenced by the analysis of DNA fragmentation, apoptotic body formation, caspase activation, and apoptosis specific changes in cell morphology is demonstrated. The depolarization of mitochondrial membrane and the release of cytochrome c were most early events in etoposide treated SGC-7901 cells, and were followed by caspase-3 activation and PARP cleavage. Caspase-8 activation was not detected under the same condition. Thus, it was proposed that etoposide induces caspase-associated apoptotic cell death in human metastatic gastric carcinoma, which is initiated by mitochondrial cytochrome c release.

关键词： Apoptosis Caspase Cytochrome c etoposide SGC-7901 cells

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Altered expression of nuclear matrix proteins in etoposide induced apoptosis in HL-60 cells

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Cell Research 2001年第2期11卷 125-134页

作者： JIN MEI LIN, PING ZHANG, MING XIAO DING, JING PING YUN, PEI FANG CHEN, YEUK HON CHEN, YIN QING CHEW College of Animal Science and Veterinary Medicine, Huazhong Agricultural University, Wuhan 430070, China College of Life Sciences, Beijing University, Beij College of Animal Science and Veterinary Medicine Huazhong Agricultural University Wuhan China Chinese University of Hong Kong Hong Kong China College of Life Sciences Beijing University Beijing China

The events of cell death and the expression of nuclear matrix protein (NMP) have been investigated in a promyelocytic leukemic cell line HL-60 induced with etoposide. By means of TUNEL assay, the nuclei displayed a characteristic morphology change, and the amount of apoptotic cells increased early and reached maximun about 39% after treatment with etoposide for 2 h. Nucleosomal DNA fragmentation was observed after treatment for 4 h. The morphological change of HL-60 cells, thus, occurred earlier than the appearance of DNA ladder. Total nuclear matrix proteins were analyzed by 2-dimensional gel electrophoresis. Differential expression of 59 nuclear matrix proteins was found in 4 h etoposide treated cells. Western blotting was then performed on three nuclear matrix acssociated proteins, PML, HSC70 and NuMA. The expression of the suppressor PML protein and heat shock protein HSC70 were significantly upregulated after etoposide treatment, while NuMA, a nuclear mitotic apparatus protein, was down regulated. These results demonstrate that significant biochemical alterations in nuclear matrix proteins take place during the apoptotic process.

关键词： Nuclear matrix protein etoposide apoptosis HL-60 cell.

Oral etoposide monotherapy is effective for metastatic breast cancer with heavy prior therapy

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Chinese Medical Journal 2012年第5期125卷 775-779页

作者： YUAN Peng XU Bing-he WANG Jia-yu MA Fei FAN Ying LI Qing ZHANG Pin Department of Medical Oncology Cancer Hospital(Institute)Chinese Academy of Medical Sciences&Peking Union Medical CollegeBeijing 100021China

Background Treatment option for metastatic breast cancer （MBC） patients pre-treated with chemotherapy is limited. Oral etoposide has shown some promises in these patients. However, patients who received heavy prior chemotherapy may have poor tolerance to prolonged oral etoposide exposure. This study is a single-arm clinical trial that evaluates the efficacy and safety of short-term oral etoposide in Chinese patients with MBC who had received heavy prior therapy.

关键词： etoposide oral metastatic breast cancer chemotherapy

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Design, Synthesis and Biological Evaluation of Novel etoposide Analogues as Cytotoxic Agents

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Chinese Journal of Chemistry 2006年第6期24卷 785-790页

作者：刘映前杨桦田瑄 State Key Laboratory of Applied Organic Chemistry Lanzhou Universitry Lanzhou Gansu 730000 China

Five novel compounds composed of etoposide and 5-fluorouracil derivatives joined by an ester linkage were prepared and evaluated for their antitumor potential. Most of these analogues have exhibited promising in vitro cytotoxic activity against cell cultures of murine leukaemia P-388 and human lung carcinoma A-549. The results presented herein challenged the long-standing structure-activity relationships, which proposed that a free 4＇-hydroxyl group is essential structural requirement for etoposide-like activity. And in addition, the 4＇-position was suggested to tolerate chemical modifications such as esterification. The preliminary testing results also indicated that the design and synthesis of these compounds were beneficial for therapeutic values of etoposide.

关键词： etoposide 5-fluorouracil amino acid antitumor drug

Anticancer Drugs (V)─—Synthesis of etoposide Derivatives

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Chemical Research in Chinese Universities 1995年第1期11卷 79-83页

作者： TIAN Xuan YAN Ze-qun LI Jin-xin and CHEN Yao-zu(National Laboratory of Applied Organic Chemistry,Lanzhou Uniuersty, Lanzhou , 730000)MU Xiao-qin(Department of Chemistry , Tianshui Teaches’ College , Tianshui , 741000) LANZHOU UNIV NATL LAB APPL ORGAN CHEMLANZHOU 730000PEOPLES R CHINA TIANSHUI TEACHERS COLL DEPT CHEMTIANSHUI 741000PEOPLES R CHINA

ＡｎｔｉｃａｎｃｅｒＤｒｕｇｓ（Ｖ）─—ＳｙｎｔｈｅｓｉｓｏｆＥｔｏｐｏｓｉｄｅＤｅｒｉｖａｔｉｖｅｓＴＩＡＮＸｕａｎ，ＹＡＮＺｅ－ｑｕｎ，ＬＩＪｉｎ－ｘｉｎａｎｄＣＨＥＮＹａｏ－ｚｕ（ＮａｔｉｏｎａｌＬａｂｏｒａｔ... 详细信息

ＡｎｔｉｃａｎｃｅｒＤｒｕｇｓ（Ｖ）─—ＳｙｎｔｈｅｓｉｓｏｆＥｔｏｐｏｓｉｄｅＤｅｒｉｖａｔｉｖｅｓＴＩＡＮＸｕａｎ，ＹＡＮＺｅ－ｑｕｎ，ＬＩＪｉｎ－ｘｉｎａｎｄＣＨＥＮＹａｏ－ｚｕ（ＮａｔｉｏｎａｌＬａｂｏｒａｔｏｒｙｏｆＡｐｐｌｉｅｄＯｒｇａｎ...

关键词： etoposide Anticancer drugs Nitroxyl radical 5-Fluorouracil

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etoposide-induced apoptosis results in chromosome breaks within the <i>AF</i>9 gene: Its implication in chromosome rearrangement in leukaemia

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Advances in Bioscience and Biotechnology 2012年第6期3卷 686-694页

作者： Cynthia Patricia Nicholas Sai-Peng Sim Faculty of Medicine and Health Sciences Universiti Malaysia Sarawak Kota Samarahan Malaysia

Treatment with etoposide (VP-16) has been associated with translocation of the mixed lineage leukaemia (MLL) gene seen in treatment-related acute myeloid leukaemia (t-AML). Among the different partner genes, AF9 is the most common partner gene of MLL. AF9 shares similar structural element with the MLL gene. Various mechanisms of translocation have been proposed for the MLL gene, including apoptosis, particularly the apoptotic nuclease. In the current study, we show that VP-16 induced cleavage of the AF9 gene in both leukaemic cells and cultured normal blood cell. All the breakpoints were mapped within the BCR1 of the AF9 gene. AF9 cleavages in leukaemic cells were abolished by pre-treatment with caspase inhibitor (Z-DEVD-FMK), suggesting the involvement of caspase-activated DNase (CAD). The absence of AF9 cleavage in K562 cells further supported the involvement of apoptosis. However, AF9 cleavages in cultured normal blood cell were not eliminated by caspase inhibitor. The possible role of CAD and other apoptotic nucleases/effectors that could be involved in AF9 translocation are discussed.

关键词： etoposide (VP-16) Apoptosis AF9 Chromosome Breaks Leukaemia