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Potentiation of PIEZO2 mechanically-activated currents in sensory neurons mediates vincristine-induced mechanical hypersensitivity

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Acta Pharmaceutica Sinica B 2023年第8期13卷 3365-3381页

作者： Mingli Duan Yurui Jia Lifang Huo Yiting Gao Jia Wang Wei Zhang Zhanfeng Jia Department of Pharmacology Hebei Medical UniversityShijiazhuang 050017China Center of Innovative Drug Research and Evaluation Institute of Medical Science and HealthHebei Medical UniversityShijiazhuang 050017China The Key Laboratory of Neural and Vascular Biology Ministry of EducationShijiazhuang 050017China The Key Laboratory of New Drug Pharmacology and Toxicology Shijiazhuang 050017China The Hebei Collaboration Innovation Center for Mechanism Diagnosis and Treatment of Neurological and Psychiatric DiseaseShijiazhuang 050017China Department of Pharmacology Institute of Chinese Integrative MedicineHebei Medical UniversityShijiazhuang 050017China

vincristine,a widely used chemotherapeutic agent for treating different cancer,often induces severe peripheral neuropathic pain.A common symptom of vincristine-induced peripheral neuropathic pain is mechanical allodynia and hyperalgesia.However,mechanisms underlying vincristine-induced mechanical allodynia and hyperalgesia are not well understood.In the present study,we show with behavioral assessment in rats that vincristine induces mechanical allodynia and hyperalgesia in a PIEZO2 channel-dependent manner since gene knockdown or pharmacological inhibition of PIEZO2 channels alleviates vincristine-induced mechanical hypersensitivity.Electrophysiological results show that vincristine potentiates PIEZO2 rapidly adapting(RA)mechanically-activated(MA)currents in rat dorsal root ganglion(DRG)neurons.We have found that vincristine-induced potentiation of PIEZO2 MA currents is due to the enhancement of static plasma membrane tension(SPMT)of these cells following vincristine treatment.Reducing SPMT of DRG neurons by cytochalasin D(CD),a disruptor of the actin filament,abolishes vincristine-induced potentiation of PIEZO2 MA currents,and suppresses vincristine-induced mechanical hypersensitivity in rats.Collectively,enhancing SPMT and subsequently potentiating PIEZO2 MA currents in primary afferent neurons may be an underlying mechanism responsible for vincristineinduced mechanical allodynia and hyperalgesia in rats.Targeting to inhibit PIEZO2 channels may be an effective analgesic method to attenuate vincristine-induced mechanical hypersensitivity.

关键词： vincristine Peripheral neuropathic pain Mechanical hypersensitivity Dorsal root ganglion neurons PIEZO2mechanically-activated currents

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Mechanism of all-transretinoic acid increasing retinoblastoma sensitivity to vincristine

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Asian Pacific Journal of Tropical Medicine 2016年第3期9卷 273-277页

作者： Yan Jiang Lin Zhang Department of Ophthalmology Ren Ji HospitalSchool of MedicineShanghai Jiao Tong University

Objective:To explore the mechanism of all-transretinoic acid(ATRA) increasing retinoblastoma(RB) sensitivity to vincristine,and the inhibiting effect of vincristine combined with ATRA treatment on the SO-RB50 cell proliferation.Methods:SO-RB50 cells were cultivated by routine culture method.Different concentrations of vincristine or ATRA were added into culture solution.After 48 h.cell counting kit-8 was used to detect the median inhibitory concentration(IC_(50)) of vincristine combined with ATRT treatment to SO-RB50 cells.SO-RB50 cells were divided into drug combination group,vincristine group,ATRA group and control group.Different drugs were added into the culture solution respectively for cell culture based on the IC_(50) value.Cell counting kit-8 was used to detect the cell proliferation every 24-h cultivation.After continuous determination for 6 d,data was processed to draw the cell growth curve.After drug use for 72 h,flow cytometry was used to detect the proportion of different cell cycles of SO-RB50 cells in each group.After drug use for 48 h,annexin V/propidium iodide method was used to detect the SO-RB50 cell apoptosis in each group.Results:The IC_(50) value of vincristine treatment on the SO-RB50 cells was 0.11 μmol/L,and ATRT was 12.84 μmol/L.The cell growth curve in control group rose gradually along with the extended culture time,but after vincristine and ATRA treatment,the cell growth curve was smooth and steady.The cell increment was the least in drug combination group and its cell growth curve was the smoothest.There was significant difference in A_(450) 48 h and 72 h after treatment(F_(grouping)=77.316,Pvincristine group,ATRA group was significantly lower(Pvincristine group was significantly increased,while the G_0/G_1 phase cell proportion was significantly decreased:the G_0/G_1 phase cell proportion in ATRA group was signific

关键词： All-transretinoic acid Retinoblastoma vincristine Cell cycle Apoptosis

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Preparation of Molecularly Imprinted Electrochemical Sensor for Detection of vincristine Based on Reduced Graphene Oxide/Gold Nanoparticle Composite Film

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Chinese Journal of Chemistry 2016年第12期34卷 1268-1276页

作者： Yan Zhang Jing Zheng Mandong Guo College of Chemistry and Material Science Shanxi Normal University Linfen Shanxi 041004 China

An innovative molecularly imprinted electrochemical sensor was fabricated based on reduced graphene oxide （RGO） and gold nanocomposite （Au） for rapid detection of vincristine （VCR）. The RGO-Au composite membrane was obtained via direct one-step electrodeposition technique of graphene oxide （GO） and chloroauric acid （HAuCl4） on the surface of a glassy carbon electrode （GCE） by means of cyclic voltammetry （CV） in the potential range be- tween -1.5 and 0.6 V in phosphate buffer solution （PBS） of pH 9.18, which is capable of effectively utilizing its superior electrical conductivity, larger specific surface area due to its synergistic effect between RGO and Au. The molecularly imprinted polymers （MIPs） were synthesized on the RGO-Au modified glassy carbon electrode surface with VCR as the template molecular, methyl acrylic acid （MAA） as the functional monomer, and ethylene glycol maleic rosinate acrylate （EGMRA） as a cross-linker. The performance of the sensor was investigated by cyclic voltammetry （CV）, differential pulse voltammetry （DPV） and electrochemical impedance spectroscopy （EIS） in de- tail. Under the optimum conditions, the fabricated sensor exhibited a linear relationship between oxidation peak current and VCR concentration over the range of 5.0×10 8 5.0×10^-6 mol.L l with a correlation coefficient of 0.9952 and a detection limit （S/N=3） of 2.6×10 8 mol.L^-1. The results indicated that the imprinted polymer films exhibited an excellent selectivity for VCR. The imprinted sensor was successfully used to determine VCR in real samples with recoveries of 90%-- 120% by using the standard addition method.

关键词： molecularly imprinted polymers electrochemical sensor reduced graphene oxide and gold nanocom-posites vincristine

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Dehydroabietic acid chemosensitizes drug-resistant acute lymphoblastic leukemia cells by downregulating survivin expression

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Asian Pacific Journal of Tropical Biomedicine 2022年第9期12卷 383-390页

作者： Li-Li Shen Wei-Hua Huang Hui-Jun Zhao Xue-Wei Yuan Department of Pediatrics Suzhou Kowloon HospitalShanghai Jiao Tong University School of MedicineSuzhouJiangsuChina

Objective:To explore the mechanism of drug resistance in acute lymphoblastic leukemia and the anti-tumor effect of combination therapy of dehydroabietic acid and vincristine against acute lymphoblastic leukemia cells.Methods:Acute lymphoblastic leukemia cells REH and CCRFCEM were employed to detect the anti-tumor effect of vincristine and doxorubicin on proliferation and apoptosis using EdU assay,human active caspase-3 Quantikine ELISA kit,and flow cytometry.vincristine-resistant REH cells(REH-R),survivin knockdown and overexpressing REH cells were established to verify the role of survivin in drug resistance.Additionally,in vitro and in vivo assays were performed to determine the effect of dehydroabietic acid on the cytotoxicity of vincristine.Results:vincristine and doxorubicin markedly suppressed proliferation and induced apoptosis of REH and CCRF-CEM cells.Survivin expression was upregulated in REH-R cells compared with REH cells.Knockdown of survivin expression obviously restored the sensitivity of REH-R cells to vincristine.Akt phosphorylation was also increased in REH-R cells compared to REH cells.In addition,LY294002,a PI3k/Akt pathway blocker,inhibited survivin expression and enhanced cytotoxicity of vincristine to REH-R cells.Dehydroabietic acid effectively reduced survivin expression in REH-R cells,thereby enhancing the therapeutic effect of vincristine on drug-resistant cells.Survivin overexpression markedly reduced the effect of dehydroabietic acid on enhancing the anti-proliferation and inducing apoptosis effect of vincristine.Moreover,the combination of dehydroabietic acid with vincristine significantly extended the survival rate in a mouse xenograft model of acute lymphoblastic leukemia,compared with vincristine treatment alone.Conclusions:Dehydroabietic acid may be used as a potential candidate for the treatment of acute lymphoblastic leukemia in combination with vincristine.

关键词： Acute lymphoblastic leukemia Drug resistance Survivin Dehydroabietic acid REH cells vincristine

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Unilateral Ptosis in a Child with Wilm’s Tumor Induced by vincristine

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Journal of Cancer Therapy 2022年第12期13卷 649-653页

作者： Aziza El Ouali Karim Lahrache Zohair El Haddar Ayad Ghannam Abdeladim Babakhouya Maria Rkain Noufissa Benajiba Department of Pediatrics Mohammed VI University Hospital Center of Oujda Oujda Morocco

vincristine is a chemotherapy drug belonging to the group of Vinca alkaloids which also includes vinblastine and vindesine. It is used in hematological malignancies and solid tumors. The Vinca alkaloids are neurotoxic, usually causing peripheral neuropathy, and rarely cranial neuropathies. We report a case of a 33-month-old male child diagnosed with Wilms’ tumor, who had an isolated unilateral right ptosis following vincristine, with a good improvement after stopping it.

关键词： Wilms’ Tumor vincristine Neuropathy Ptosis

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Effect of Salvia officinalis Hydroalcoholic Extract on vincristine-induced Neuropathy in Mice

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中国天然药物 2011年第5期9卷 354-358页

作者： Ali Namvaran Abbas Abad Mir Hadi Khayate Nouri Farzaneh Tavakkoli Young Researchers Club Tabriz BranchIslamic Azad UniversityTabrizIran Pharmacology & Toxicology Department Veterinary Faculty of Islamic Azad UniversityTabriz branchTabriz-Iran Department of Pharmacology & Toxicology Faculty of Veterinary MedicineTabriz BranchIslamic Azad UniversityTabriz-Iran

AIM:vincristine is one of the most commonly used chemotherapeutic drugs to treat a variety of malignant diseases,including leukemia and lymphoma.Studies have shown that vincristine cause painful effects,whereas Salvia officinalis(SO) showed analgesic and anti-inflammatory effects.The aim of this study is to investigate the effects of the SO hydro-alcoholic extract on vincristine-induced peripheral neuropathy in mice in comparison with morphine.METHODS:Experiments were performed on 60 NMRI male mice weighing 25-30 g divided into six groups.The individual groups received normal saline,SO hydro-alcoholic extract,vincristine,SO hydro-alcoholic extract and vincristine(12 days before formalin test),morphine,and vincristine and morphine,respectively.The injected hind paw biting and licking was measured in a 5-minute interval for one hour.RESULTS:The results showed that formalin induce significant(P vincristine caused significant(P vincristine showed that SO significantly(P vincristine-induced pain.Morphine decreased vincristine-induced pain in the first and second phase of formalin test significantly(P vincristine showed analgesic and painful neuropathic effects,suggesting that SO extract could be useful in the treatment of vincristine-induced peripheral neuropathic pain.

关键词： Salvia officinalis vincristine Pain Morphine Mice

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Folic acid-conjugated liposomal vincristine for multidrug resistant cancer therapy

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Asian Journal of Pharmaceutical Sciences 2013年第2期8卷 118-127页

作者： Chenyu Wang Linglin Feng Xiangkun Yang Fei Wang Weiyue Lu Department of Pharmaceutics School of PharmacyFudan UniversityKey Laboratory of Smart Drug Delivery(Fudan University)Ministry of Education&PLAShanghai 201203China State Key Laboratory of Molecular Engineering of Polymers(Fudan University) Shanghai 200433China Shanghai Institute of Planned Parenthood Research Key Laboratory of Contraceptives and Devices ResearchNPFC of ChinaShanghai 200032China

We encapsulated vincristine into folic acid-conjugated PEGylated liposomes to improve the anti-tumor efficacy on multidrug resistant cancers.It was observed that the drug delivery system we constructed exhibited maximum cytotoxicity on KBv200 cells(multidrug resistant variant)compared with any other formulations.The semi-quantitative analysis of region of interest revealed that there was a great increase in area under curve(AUC)of a near-infrared fluorescein in solid tumors due to folic acid-mediated accumulation.Folic acid-conjugated PEGylated liposomes showed a significant tumor growth inhibiting effect in vitro and in vivo.TUNEL assay revealed that folic acid-conjugated PEGylated liposomes could induce cell apoptosis much more greatly than others.This study demonstrated that it had potential application prospective for the treatment of multidrug resistant cancer.

关键词： Multidrug resistance Folic acid Liposome vincristine Targeting delivery Pharmacodynamics

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构建重定向的NF-κB/OIP5表达程序以增强化疗对膀胱癌的治疗效果

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Science Bulletin 2023年第24期68卷 3207-3224,M0006页

作者：郑彬彬牛立慢徐海波杨育宾陈延萍王晨光陈巍黄卫人 Department of Urology Shenzhen Institute of Translational MedicineShenzhen Second People’s HospitalThe First Affiliated Hospital of Shenzhen UniversityInternational Cancer Center of Shenzhen UniversityShenzhen 518039China Shenzhen Institute of Synthetic Biology Shenzhen Institutes of Advanced TechnologyChinese Academy of SciencesShenzhen 518055China Guangdong Key Laboratory of Systems Biology and Synthetic Biology for Urogenital Tumors Shenzhen 518035China

NF-κB是重要的转录调控因子,对下游肿瘤耐药基因起关键调控作用.基于CRISPR基因编辑技术,可在膀胱癌中构建人工合成的基因表达程序,以重编程肿瘤药物应答过程.本研究发现Opa相互作用蛋白5(OIP5)在NF-κB激活后上调,并引起膀胱癌对长春... 详细信息

NF-κB是重要的转录调控因子,对下游肿瘤耐药基因起关键调控作用.基于CRISPR基因编辑技术,可在膀胱癌中构建人工合成的基因表达程序,以重编程肿瘤药物应答过程.本研究发现Opa相互作用蛋白5(OIP5)在NF-κB激活后上调,并引起膀胱癌对长春新碱耐药.通过整合连接靶向OIP5的引导RNA与NF-κB的适配体RNA,成功获得兼具编码靶向位点和调控功能的模块化RNA.此模块化RNA可识别并与长春新碱活化的NF-κB相结合,促使NF-κB从上调逆转为下调OIP5表达,并阻断多条NF-κB介导的耐药通路,从而高效阻止肿瘤耐药的发生.本研究还开发了一种纳米递药系统共递送模块化RNA和长春新碱,体内外实验表明两者协同增强药物的抗肿瘤疗效.通过基于纳米递药系统的联合治疗策略,我们证实了CRISPR技术在膀胱癌中构建人工合成基因表达程序的有效性,可重编程肿瘤的药物应答过程,达到增强膀胱癌化疗敏感性的目的.

关键词： Drug resistance Gene circuit RNA engineering NF-jB OIP5 vincristine

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CHEMOTHERAPY FOR ADVANCED NASOPHARYNGEAL CARCINOMA WITH METHOTREXATE, vincristine, CISPLATIN AND ADRIAMYCIN

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Chinese Journal of Cancer Research 2002年第2期14卷 145-148页

作者：苏勇张锦明夏云飞朱荣钱朝南莫浩元 Cancer Center Zhongshan University of Medical Sciences Guangzhou

Objective: To evaluate the efficacy and toxicity of M-VCA (methortrexate 30 mg/m2, vincristine 2 mg, cisplatin 70 mg/m2, adriamycin 30 mg/m2) combination chemotherapy for advanced nasopharyngeal carcinoma. Methods: Thirty-five patients with advanced nasopharyngeal carcinoma, including 11 patients with untreated local advanced nasopharyngeal carcinoma and 24 patients with local-regional recurrent or metastatic nasopharyngeal carcinoma, received the chemotherapy of M-VCA. The cycle was repeated on day 22 for two cycles. All patients completed the chemotherapy courses. Results: The overall response rate was 75%, with untreated local advanced nasopharyngeal carcinomas 11/11(100%), local-regional recurrent nasopharyngeal carcinomas 12/18(67%), lung metastases 8/9(89%), bone metastases 5/9(56%), and liver metastases 1/2(50%). The main side effects included mild to moderate degree alopecia, nausea/vomiting, and neutropenia. Conclusion: M-VCA is well tolerated and has good efficacy for advanced nasopharyngeal carcinoma and is worth investigating further.

关键词： Nasopharyngeal neoplasm Combination chemotherapy Methotrexate vincristine Cisplatin Adriamycin

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Biosynthetic pathway of terpenoid indole alkaloids in Catharanthus roseus

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Frontiers of Medicine 2014年第3期8卷 285-293页

作者： Xiaoxuan Zhu Xinyi Zeng Chao Sun Shilin Chen Institute of Medicinal Plant Development China Academy of Medical Sciences & Peking Union Medical College Beijing 100193 China Institute of Chinese Materia Medica China Academy of-Chinese Medical Sciences Beijing 100700 China

Catharanthus roseus is one of the most extensively investigated medicinal plants, which can produce more than 130 alkaloids, including the powerful antitumor drugs vinblastine and vincristine. Here we review the recent advances in the biosynthetic pathway of terpenoid indole alkaloids （TIAs） in C. roseus, and the identification and characterization of the corresponding enzymes involved in this pathway. Strictosidine is the central intermediate in the biosynthesis of different TIAs, which is formed by the condensation of secologanin and tryptamine. Secologanin is derived from terpenoid （isoprenoid） biosynthetic pathway, while tryptamine is derived from indole biosynthetic pathway. Then various specific end products are produced by different routes during downstream process. Although many genes and corresponding enzymes have been characterized in this pathway, our knowledge on the whole TIA biosynthetic pathway still remains largely unknown up to date. Full elucidation of TIA biosynthetic pathway is an important prerequisite to understand the regulation of the TIA biosynthesis in the medicinal plant and to produce valuable TIAs by synthetic biological technology.

关键词： Catharanthus roseus terpenoidindole alkaloids biosynthetic pathway vinblastine vincristine

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