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Isorhapontigenin protects against doxorubicin-induced cardiotoxicity via increasing YAP1 expression

Acta Pharmaceutica Sinica B 2021年第3期11卷 680-693页

作者： Panxia Wang Minghui Wang Yuehuai Hu Jianxing Chen Yanjun Cao Cui Liu Zhongkai Wu Juan Shen Jing Lu Peiqing Liu School of Pharmaceutical Sciences Sun Yat-sen UniversityGuangzhou 5/0006China Department of Cardiac Surgery First Affiliated HospitalSun Yat-sen UniversityGuangzhou 510080China Guangdong Provincial Key Laboratory of Pharmaceutical Bioactive Substances Guangdong Pharmaceutical UniversityGuangzhou 510006China Guangdong Provincial Key Laboratory of New Drug Design and Evaluation Sun Yat-sen UniversityGuangzhou 510006China Guangdong Provincial Engineering Laboratory of Druggability and New Drugs Evaluation Guangzhou 510006China

As an effective anticancer drug, the clinical limitation of doxorubicin(Dox) is the time-and dose-dependent cardiotoxicity. Yes-associated protein 1(YAP1) interacts with transcription factor TEA domain 1(TEAD1) and plays an important role in cell proliferation and survival. However, the role of YAP1 in Dox-induced cardiomyopathy has not been reported. In this study, the expression of YAP1 was reduced in clinical human failing hearts with dilated cardiomyopathy and Dox-induced in vivo and in vitro cardiotoxic model. Ectopic expression of Yap1 significantly blocked Dox-induced cardiomyocytes apoptosis in TEAD1 dependent manner. Isorhapontigenin(Isor) is a new derivative of stilbene and responsible for a wide range of biological processes. Here, we found that Isor effectively relieved Doxinduced cardiomyocytes apoptosis in a dose-dependent manner in vitro. Administration with Isor(30 mg/kg/day, intraperitoneally, 3 weeks) significantly protected against Dox-induced cardiotoxicity in mice. Interestingly, Isor increased Dox-caused repression in YAP1 and the expression of its target genes in vivo and in vitro. Knockout or inhibition of Yap1 blocked the protective effects of Isor on Dox-induced cardiotoxicity. In conclusion, YAP1 may be a novel target for Dox-induced cardiotoxicity and Isor might be a new compound to fight against Dox-induced cardiotoxicity by increasing YAP1 expression.

关键词： Isorhapontigenin YAP1 doxorubicin Cardiotoxicity Cardiomyocytes apoptosis TEAD1 Connective tissue growth factor Amphiregulin

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Melatonin and doxorubicin synergistically induce cell apoptosis in human hepatoma cell lines

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World Journal of Gastroenterology 2010年第12期16卷 1473-1481页

作者： Fan, Lu-Lu Sun, Guo-Ping Wei, Wei Wang, Zhang-Gui Ge, Lei Fu, Wei-Zheng Wang, Hua Anhui Med Univ Affiliated Hosp 1 Dept Oncol Hefei 230022 Anhui Peoples R China Anhui Med Univ Inst Clin Pharmacol Key Lab Res & Dev Chinese Med Key Lab Antiinflammatory & Immunol Pharmacol Hefei 230022 Anhui Peoples R China Anhui Med Univ Affiliated Prov Hosp Dept Oncol Hefei 230032 Peoples R China

AIM:To investigate whether Melatonin has synergistic effects with doxorubicin in the growth-inhibition and apoptosis-induction of human hepatoma cell lines HepG2 and Bel-7402.METHODS:The synergism of Melatonin and doxorubicin inhibited the cell growth and induced cell apoptosis in human hepatoma cell lines HepG2 and Bel-7402.Cell viability was analyzed by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-tetrazolium bromide(MTT)assay.Cell apoptosis was evaluated using TUNEL method and flow cytometry.Apoptosis-related protein Bax,Bcl-2 and caspase-3 expressions were measured by immunohistochemical staining.RESULTS:Treatment with Melatonin(10 -8 -10 -5 mol/L) alone had a dose-related inhibitory effect on cell proliferation but no cytotoxic effect on hepatoma cell lines HepG2 and Bel-7402.Interestingly,when combined with doxorubicin,Melatonin significantly increased the effects of cell growth inhibition and cell apoptosis.Furthermore,TUNEL staining and flow cytometry revealed that cooperative apoptosis induction was associated with decreased expression of Bcl-2 as well as increased expression of Bax and Caspase3.CONCLUSION:The synergism of Melatonin and doxorubicin inhibits hepatoma cell growth and induces cell apoptosis.

关键词： Melatonin doxorubicin Human hepatoma cell line Apoptosis

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Simultaneous determination of doxorubicin and its dipeptide prodrug in mice plasma by HPLC with fluorescence detection

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Journal of Pharmaceutical Analysis 2016年第3期6卷 199-202页

作者： Jing Han Jue Zhang Haiyan Zhao Yan Li Zilin Chen Key Laboratory of Combinatorial Biosynthesis and Drug Discovery (Wuhan University) Ministry of Education School of Pharmaceutical Sciences Wuhan University Wuhan 430071 China Wuhan University Zhongnan Hospital Wuhan 430071 China

A simple and sensitive high performance liquid chromatography with fluorescence detection （HPLC-FD） has been developed for simultaneous quantification of doxorubicin （DOX） and its dipeptide conjugate prodrug （PDOX） in mice plasma. The chromatographic separation was carried out on an Amethyst C18-H column with gradient mobile phase of 0.1% formic acid and 0.1% formic acid in acetonitrile at a flow rate of 1.0 mL/min. The excitation and emission wavelengths were set at 490 and 550 nm, respectively. The method was comprehensively validated. The limits of detection were low up to 5.0 ng/mL for DOX and 25.0 ng/mL for PDOX. And the limits of quantification were low up to 12.5 ng/mL for DOX and 50 ng/mL for PDOX, which were lower than those for most of the current methods. The calibration curves showed good linearity （R2 〉 0.999） over the concentration ranges. The extraction recoveries ranged from 84.0% to 88.2% for DOX and from 85.4% to 89.2% for PDOX. Satisfactory intra-day and inter-day precisions were achieved with RSDs less than 9.1%. The results show that the developed HPLC-FD method is accurate, reliable and will be helpful for preclinical pharmacokinetic study of DOX and PDOX.

关键词： doxorubicin doxorubicin＇s dipeptide prodrug HPLC-FD Mice plasma

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Paclitaxel-doxorubicin sequence is more effective in breast cancer cells with heat shock protein 27 overexpression

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Chinese Medical Journal 2008年第20期121卷 1975-1979页

作者： SHI Peng WANG Ming-ming JIANG Li-yu LIU Huan-tao SUN Jing-zhong Department of General Surgery Provincial Hospital Affiliated to Shandong University Jinan Shandong 250021 China Department of Breast Surgery Qilu Hospital Shandong University Jinan Shandong 250012 China

Background Cancer cells with overexpression of heat shock protein 27 （HSP27） are resistant to chemotherapeutic drug doxorubicin （Dox）. Paclitaxel （Pacl） was reported to suppress HSP27 expression in ovarian and uterine cancer cells. The purposes of this study were to investigate whether Pacl inhibits the expression of HSP27 in breast cancer cells, whether Pacl can sensitize breast cancer cells with HSP27 overexpression to Dox, and to define a more effective schedule for the combination of Dox with Pacl. Methods The HSP27 high-expressing human breast cancer cell lines, MCF-7 and MDA-MB-435, and the HSP27 low-expressing cell line, MDA-MB-231, were used in this study. The level of HSP27, topoisomerase （Topo） IIα and β expression were assessed by Western blotting. The cytotoxic activities of Dox, Pacl and combination of these two drugs were evaluated by 3-（4,5-dimethylthiazol-2-yl）-2,5-diphenyltetrazolium bromide assay and flow cytometric assays. Results Pacl （0.1 μmol/L） inhibited HSP27 expression by approximately 2-fold in MCF-7 and MDA-MB-435 cells, while up-regulating the level of topo IIα and β. In contrast, expression of HSP27 in MDA-MB-231 did not change significantly following Pacl treatment. There were synergistic effects in both treatment sequences （Pacl-Dox and Dox-Pacl） when Pacl was combined with Dox. Compared with those treated with the Dox-Pacl sequence, the Pacl-Dox sequence had a stronger effect in cancer cells with HSP27 overexpression, as MCF-7 and MDA-MB-435 treated with the Pacl-Dox sequence had lower viabilities and a higher apoptotic rate. Conclusions Paclitaxel significantly decreases the level of HSP27 in breast cancer cells overexpressing HSP27. In combination therapies, the Pacl-Dox sequence is more effective in clearing breast cancer cells with high HSP27 expression compared with the Dox-Pacl sequence.

关键词： apoptosis doxorubicin heat shock protein 27 paclitaxel drug resistance

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Xinfuli improves cardiac function, histopathological changes and attenuate cardiomyocyte apoptosis in rats with doxorubicin-induced cardiotoxicity

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Journal of Geriatric Cardiology 2016年第12期13卷 968-972页

作者： Pei-Pei LU Jie MA Xiao-Peng LIANG Cai-Xia GUO Yan-Kun YANG Kun-Qi YANG Qi-Ming SHEN Li-Hong MA Xian-Liang ZHOU Department of Traditional Chinese Medicine State Key Laboratory of Cardiovascular Disease Fuwai Hospital National Center for Cardiovascular DiseasesChinese Academy of Medical Sciences and Peking Union Medical College Beijing China Department of Cardiology State Key Laboratory of Cardiovascular Disease Fuwai Hospital National Center for Cardiovascular D&eases Chinese Acad-emy of Medical Sciences and Peking Union Medical College Beijing China

Xinfuli 小粒(XG ) ，一副复合中草药，有效地为心失败的处理在中国被使用超过五十年了。试图带着导致doxorubicin 的 cardiotoxicity.MethodsSprague-Dawley 老鼠在老鼠调查效果和 Xinfuli 的内在的机制的这研究与 doxorubicin 的 int... 详细信息

Xinfuli 小粒(XG ) ，一副复合中草药，有效地为心失败的处理在中国被使用超过五十年了。试图带着导致doxorubicin 的 cardiotoxicity.MethodsSprague-Dawley 老鼠在老鼠调查效果和 Xinfuli 的内在的机制的这研究与 doxorubicin 的 intraperitoneal 注射被对待(纪录影片， 2.5 mg/kg 每星期)为六个星期，然后随机把 intragastrically 收到了正常的管理的组划分了成四盐(控制组)或 XG 的不同剂量( 0.675 g/kg 每天， 1.35 g/kg 每天，和 2.7g/kg 每天，分别地)为六个星期。Transthoracic echocardiography 被执行室的部分弄短评估左(LVFS ) 并且在 XG 处理和组织病理学说的变化前后的左室的喷射部分(LVEF ) 也被检验。心肌的房间 apoptosis 被染色的 TUNEL 检测。相关基因和蛋白质的表达式在控制组，用 immunohistochemical staining.ResultsCompared 被分析到那些在对待的组显著地显示出的 XG 的老鼠改进了心脏的功能和更温和的心脏的组织病理学说的变化，更低的 cardiomyocyte apoptosis 索引， Bcl-2 的更高的表示和 XG 的 Bax.ConclusionsAdministration 的更低的表示与导致doxorubicin 的 cardiotoxicity 在老鼠改进心脏的功能和组织病理学说的变化。这些效果与 cardiomyocyte apoptosis 的抑制被联系，也许经由 Bcl-2 和 Bax 蛋白质表示的规定。

关键词： Apoptosis doxorubicin 心失败草药的药

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Protective effect of chrysoeriol against doxorubicin-induced cardiotoxicity in vitro

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Chinese Medical Journal 2009年第21期122卷 2652-2656页

作者： LIU Zhe SONG Xiao-dong XIN Ying WANG Xiao-jian YU Hui BAI Yong-yi LIU Jun-hao HANG Chan-na HUI Ru-tai Sino-German Laboratory for Molecular Medicine Key Laboratory for Clinical Cardiovascular Genetics of Ministry of Education Cardiovascular Institute & Fu Wai Hospital Chinese Academy of Medical Sciences Peking Union Medical College Beijing 100037 China

Background The use of doxorubicin （DOX） is limited by its dose-dependent cardiotoxicity. Reactive oxygen species （ROSs） play an important role in the pathological process of DOX-induced cardiotoxicity. The aim of this study was to evaluate the protective effect of chrysoeriol, a flavone compound, against DOX-induced apoptosis and death in H9c2 cells and to find out its preliminary mechanism. Methods We used 3-（4,5-dimethylthiazol-2-yl）-2,5-diphenyl-2H-tetrazolium bromide （MTT） assay, Hoechst33258 staining and measurement of lactate dehydrogenase （LDH） release to evaluate the protective effect of chrysoeriol against DOX-induced apoptosis and death in H9c2 cells. To find out the mechanism of this protective effect, we observed the immunofluorescence of intracellular ROS and measured the activities of malondialdehyde （MDA）, superoxide dismutase （SOD） and glutathione peroxidase （GPx）. Furthermore, we evaluated the effect of chrysoeriol on the antitumor activity of DOX in HeLa cells with MTT assay. Results The results of MTT assay, Hoechst 33258 staining and measurement of LDH release showed that chrysoeriol significantly reduced doxorubicin-induced apoptosis and cell death. Chrysoeriol at a dose of 20 μg/ml notably reduced intracellular ROS, decreased the concentration of MDA in the supernatant of DOX-treated H9c2 cells and increased SOD and GPx activities to their normal levels. Further study showed that the addition of chrysoeriol did not affect the antitumor activity of DOX. Conclusion Chrysoeriol could potentially serve as a novel cardioprotective agent against DOX-induced cardiotoxicity without affecting the antitumor activity of DOX.

关键词： chrysoeriol doxorubicin cardiotoxicity reactive oxygen species

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Anti-Cancer Effects of Novel doxorubicin Prodrug PDOX in MCF-7 Breast Cancer Cells

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Journal of Huazhong University of Science and Technology(Medical Sciences) 2014年第4期34卷 521-528页

作者：张珏何良耿霞飞 Raymond A. Firestone 洪亚平李雁 Department of Oncology Zhongnan Hospital of Wuhan University Nanjing Meihua Pharmaceuticals Ltd Hubei Key Laboratory of Tumor Biological Behaviors & Hubei Cancer Clinical Study Center

Ac-Phe-Lys-PABC-DOX（PDOX） is a smart doxorubicin（DOX） prodrug designed to decrease toxicities while maintaining the potent anticancer effects of DOX. This study was aimed at elucidating the effectiveness and toxicities of DOX and PDOX in patient-derived MCF-7 breast cancer cells in vitro. The MCF-7 cells were exposed to both PDOX and DOX, and cytotoxicities, cell cycle and P53/P21 signaling alterations were studied. Abundant cathepsin B was found in the MCF-7 cells, and treatment with PDOX and DOX triggered dose- and time-dependent cytotoxicity and resulted in a significant reduction in cell viability. The IC50 of PDOX and DOX was 3.91 and 0.94 μmol/L, respectively. Both PDOX and DOX caused an up-regulation of the P53/P21-related signal pathway, and PDOX significantly increased expression of P53 and caspase 3, and arrested the cell cycle at the G1/G2 phase. As compared with DOX, PDOX reduced toxicities, and it may have different action mechanisms on breast cancer cells.

关键词： breast cancer doxorubicin prodrug molecular targeted therapy cathepsin B

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Characterization of synergistic anti-tumor effects of doxorubicin and p53 via graphene oxide-polyethyleneimine nanocarriers

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Journal of Materials Science & Technology 2017年第8期33卷 807-814页

作者： Bei Xie Jipeng Yi Jian Peng Xing Zhang Lei Lei Dapeng Zhao Zhixin Lei Hemin Nie Institute of Bionanotechnology and Tissue Engineering College of Life SciencesHunan UniversityChangsha 410082China Shenyang National Laboratory for Materials Science Institute of Metal ResearchChinese Academy of SciencesShenyang 110016China Department of Orthodontics Xiangya Stomatological HospitalCentral South UniversityChangsha 410008China Changsha DMY Medical Technology Co.Ltd Changsha 410005China Shenzhen Research Institute of Hunan University Nanshan Hi-new Technology and Industry ParkShenzhen 518057China

Co-delivery of chemical drugs and therapeutic genes for synergistic therapy provides a promising strategy to treat devastating diseases. However, the real-time coordination patterns between chemical drugs and therapeutic genes remain poorly understood. Herein, the complexes of doxorubicin/graphene oxidepolyethyleneimine/p53 plasmid（Dox/GO-PEI/p53） were fabricated and employed to investigate the synergistic manner between Dox and p53 in the inhibition of He La cell growth. GO was conjugated with PEI to form the GO-PEI backbone as the delivery vector. The GO backbone provided surfaces with a high specific area to load Dox via the π-π stacking interaction, and was able to release Dox significantly faster at pH 5.0 than at pH 7.0, while the positively charged PEI section of GO-PEI could condense plasmids into GO-PEI/DNA nanoparticles via the electrostatic interaction. The nanoparticles efficiently mediated the transfection of DNA in He La cells, with lower cytotoxicity compared to PEI/DNA nanoparticles. Furthermore, the complexes of Dox/GO-PEI/p53 released Dox and expressed p53 gene in a sequential manner,and showed successive inhibition of the in vitro growth of He La cells. This type of drug/GO-PEI/DNA complex can be employed as a platform to investigate the coordination pattern between chemical drugs and therapeutic genes for tumor therapy.

关键词： Graphene oxide Polyethyleneimine doxorubicin p53 Successive inhibition

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NOVEL pH-SENSITIVE DRUG DELIVERY SYSTEM BASED ON NATURAL POLYSACCHARIDE FOR doxorubicin RELEASE

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Chinese Journal of Polymer Science 2008年第3期26卷 369-374页

作者：樊渝江 National Engineering Research Center for Biomaterials Engineering Research Center of BiomaterialsSichuan UniversityChengdu 610064China

A novel pH-sensitive nanoparticle drug delivery system (DDS) derived fl om natural polysaccharide pullulan for doxorubicin (DOX) release was prepared.Pullulan was functionalized by successive carboxymethylization and amidation to introduce hydrazide groups.DOX was then grafted onto pullulan backbone through the pH-sensitive hydrazone bond to form a pullulan/DOX conjugate.This conjugate self-assembled to form nano-sized particles in aqueous solution as a result of the hydrophobic interaction of the DOX.Trans...

关键词： Natural polysaccharide pH-sensitive Nanoparticle drug delivery system doxorubicin

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Sarcoma stratification by combined pH2AX and MAP17(PDZK1IP1)levels for a better outcome on doxorubicin plus olaparib treatment

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Signal Transduction and Targeted Therapy 2020年第1期5卷 697-709页

作者： Marco Perez JoséManuel García-Heredia Blanca Felipe-Abrio Sandra Muñoz-Galván Javier Martín-Broto Amancio Carnero Instituto de Biomedicina de Sevilla(IBIS) Hospital Universitario Virgen del RocíoUniversidad de SevillaConsejo Superior de Investigaciones CientíficasSevillaSpain Ciber de Cancer IS Carlos IIIMadridSpain Departamento de Bioquímica Vegetal y Biología Molecular Universidad de SevillaSevillaSpain Departamento de Anatomía Patológica Hospital Universitario Virgen del RocíoSevillaSpain

Sarcomas constitute a rare heterogeneous group of tumors,including a wide variety of histological subtypes.Despite advances in our understanding of the pathophysiology of the disease,first-line sarcoma treatment options are still limited and new treatment approaches are needed.Histone H2AX phosphorylation is a sensitive marker for double strand breaks and has recently emerged as biomarker of DNA damage for new drug development.In this study,we explored the role of H2AX phosphorylation at Ser139 alone or in combination with MAP17 protein,an inducer of DNA damage through ROS increase,as prognostic biomarkers in sarcoma tumors.Next,we proposed doxorubicin and olaparib combination as potential therapeutic strategies against sarcomas displaying high level of both markers.We evaluate retrospectively the levels of pH2AX(Ser139)and MAP17 in a cohort of 69 patients with different sarcoma types and its relationship with clinical and pathological features.We found that the levels of pH2AX and MAP17 were related to clinical features and poor survival.Next,we pursued PARP1 inhibition with olaparib to potentiate the antitumor effect of DNA damaging effect of the DNA damaging agent doxorubicin to achieve an optimal synergy in sarcoma.We demonstrated that the combination of olaparib and doxorubicin was synergistic in vitro,inhibiting cell proliferation and enhancing pH2AX intranuclear accumulation,as a result of DNA damage.The synergism was corroborated in patient-derived xenografts(PDX)where the combination was effective in tumors with high levels of pH2AX and MAP17,suggesting that both biomarkers might potentially identify patients who better benefit from this combined therapy.

关键词： H2AX doxorubicin treatment

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