公共科学图书馆

58.PraziquantelSynergisticallyEnhancesPaclitaxelEfficacytoInhibitCancerCellGrowth吡喹酮增强紫杉醇疗效协同抑制癌细胞的生长PLOSONE2012《公共科学图书馆•综合2012》Abstract摘要Themajorchallengeswearefacingincancertherapywithpaclitaxel(PTX)arethedrugresistanceandseveresideeffects.MassiveeffortshavebeenmadetoovercometheseclinicalchallengesbycombiningPTXwithotherdrugs.Inthisstudy,wereportedthefirstpreclinicaldatathatpraziquantel(PZQ),ananti-parasiteagent,couldgreatlyenhancetheanticancerefficacyofPTXinvariouscancercelllines,includingPTX-resistantcelllines.Basedonthecombinationindexvalue,wedemonstratedthatPZQsynergisticallyenhancedPTX-inducedcellgrowthinhibition.Theco-treatmentofPZQandPTXalsoinducedsignificantmitoticarrestandactivatedtheapoptoticcascade.Moreover,PZQcombinedwithPTXresultedinamorepronouncedinhibitionoftumorgrowthcomparedwitheitherdrugaloneinamousexenograftmodel.WetriedtoinvestigatethepossiblemechanismsofthissynergisticefficacyinducedbyPZQandPTX,andwefoundthatthecotreatmentofthetwodrugscouldmarkedlydecreaseexpressionofX-linkedinhibitorofapoptosisprotein(XIAP),anantiapoptoticprotein.Ourdatafurtherdemonstratedthatdown-regulationofXIAPwasrequiredforthesynergisticinteractionbetweenPZQandPTX.Together,thisstudysuggestedthatthecombinationofPZQandPTXmayrepresentanovelandeffectiveanticancerstrategyforoptimizingPTXtherapy.我们面临的主要挑战是用紫杉醇(PTX)治疗癌症时的抗药性和严重的副作用。大量努力用在克服这些临床挑战，通过将PTX与其他药物结合。在这项研究中，我们首先报道了吡喹酮的临床前数据(PZQ)，一种抗寄生虫药，可以大大增强PTX在各种癌症细胞系，包括PTX-resistant细胞系中的抗癌疗效。基于组合索引值，我们证明了PZQ协同增强PTX-induced细胞生长抑制。PZQ和PTX的联合治疗也诱导了显著的有丝分裂阻滞和激活凋亡级联。此外，PZQ与PTX结合会导致更加明显地抑制肿瘤的生长相比在鼠移植瘤模型中的其它单独用药。我们试图调查PZQ和PTX引起的协同疗效的可能机制，同时我们发现这两种药物的联合治疗可以显著减少凋亡蛋白(XIAP)中伴X染色体的抑制的表达，一种抗凋亡蛋白。我们的数据进一步表明，XIAP下调变化是PZQ和PTX间协同互用之所需。总之，本研究表明PZQ和PTX的组合可能会呈现一种新颖有效的抗癌策略从而优化PTX治疗。59.CombinedDeliveryofPaclitaxelandTanespimycinviaMicellarNanocarriers:Pharmacokinetics,EfficacyandMetabolomicAnalysis通过微胞载体结合传送紫杉醇和坦螺旋霉素:药物动力学、疗效和代谢物组学分析。PLOSONE2013《公共科学图书馆•综合2013》Abstract摘要Background:Despitethepromisinganticancerefficacyobservedinpreclinicalstudies,paclitaxelandtanespimycin(17-AAG)combinationtherapyhasyieldedmeagerresponsesinaphaseIclinicaltrial.Oneseriousproblemassociatedwithpaclitaxel/17-AAGcombinationtherapyistheemploymentoflargequantitiesoftoxicorganicsurfactantsandsolventsfordrugsolubilization.Thegoalofthisstudywastoevaluateamicellarformulationfortheconcurrentdeliveryofpaclitaxeland17-AAGinvivo.Methodology/PrincipalFindings:Paclitaxel/17-AAG-loadedmicelleswereassessedinmicebearinghumanovariantumorxenografts.Comparedwiththefreedrugsatequivalentdoses,intravenousadministrationofpaclitaxel/17-AAG-loadedmicellesledto3.5-and1.7-foldincreaseinthetumorconcentrationsofpaclitaxeland17-AAG,respectively,withoutsignificantalteringdruglevelsinnormalorgans.Theenhancedtumoraccumulationofthemicellardrugswasfurtherconfirmedbythewhole-bodynearinfraredimagingusingindocyaninegreen-labeledmicelles.Subsequently,theanticancerefficacyofpaclitaxel/17-AAG-loadedmicelleswasexaminedincomparisonwiththefreedrugs(weekly20mg/kgpaclitaxel,twice-weekly37.5mg/kg17-AAG).Wefoundthatpaclitaxel/17-AAG-loadedmicellescausednear-completearrestoftumorgrowth,whereasthefreedrug-treatedtumorsexperiencedrapidgrowthshortlyafterthe3-weektreatmentperiodended.Furthermore,comparativemetabolomicprofilingbyprotonnuclearmagneticresonancerevealedsignificantdecreaseinglucose,lactateandalaninewithsimultaneousincreaseinglutamine,glutamate,aspartate,choline,creatineandacetatelevelsinthetumorsofmicetreatedwithpaclitaxel/17-AAG-loadedmicelles.Conclusions/Significance:Wehavedemonstratedinthecurrentwokasafeandefficaciousnano-sizedformulationforthecombineddeliveryofpaclitaxeland17-AAG,anduncovereduniquemetabolomicsignaturesinthetumorthatcorrelatewiththefavorabletherapeuticresponsetopaclitaxel/17-AAGcombinationtherapy.背景:尽管有希望的抗癌疗效在临床前研究中被观察过，但紫杉醇和坦螺旋霉素(17-AAG)的联合治疗在第一阶段的临床试验中取得了微薄的反应。一个严重的问题：紫杉醇与17-AAG联合治疗是使用大量有毒的有机表面活性剂和溶剂来溶解药物。本研究的目的是鉴定在活的有机体内并发形成的紫杉醇和17-AAG的微胞剂型。方法论/主要结果:紫杉醇/17-AAG-loaded微粒在忍受人类卵巢移植瘤的小鼠中被评定。相比等效剂量的免费药物,静脉注射紫杉醇/17-AAG-loaded微粒将导致3.5——1.7倍增加在肿瘤里紫杉醇和17-AAG的浓度，却没有显著改变各自在正常器官的药物水平。增大的肿瘤积累的微胞药物通过使用吲哚菁绿示踪的微粒全身近红外线成像被进一步证实。随后，紫杉醇的抗癌功效/17-AAG-loaded微粒被检测后与免费的药物相比较(每周20毫克/公斤紫杉醇，每周37.5毫克/公斤17-AAG)。我们发现紫杉醇/17-AAG-loaded微粒导致几乎完全被逮捕,肿瘤的生长,而免费药物治疗肿瘤经历了快速增长3周治疗期结束后不久。我们发现紫杉醇/17-AAG-loaded微粒导致几乎完全阻止肿瘤的生长，而免费治疗肿瘤的药物在经历3周治疗期结束后不久快速增长。此外，对比代谢物组学性能分析，通过质子核磁共振显示葡萄糖、乳酸和丙氨酸显著降低，同时用紫杉醇/17-AAG-loaded微粒治疗的鼠肿瘤里谷氨酰胺、谷氨酸、天冬氨酸、胆碱、肌酸和醋酸含量增加。结论/意义:我们演示了当前阶段安全而有效的纳米级剂型即紫杉醇和17-AAG的组合传送，并在肿瘤里发现了独特的代谢物组学特征即紫杉醇/17-AAG组合疗法与有利的治疗反应的对应关系。60.SynergisticEffectsofApigeninandPaclitaxelonApoptosisofCancerCells芹黄素和紫杉醇对癌症细胞凋亡的协同影响PLoSONE2011《公共科学图书馆•综合2011》Abstract摘要Background:Itwaswellknownthattheclinicaluseofchemotherapeuticdrugsisrestrictedbysevereadversereactionsanddrugresistances.Thusitisnecessarytofigureoutastrategytoincreasethespecificanti-tumorefficiencyofchemotherapeuticdrugs.Apigenin,akindofflavonoids,hasbeenreportedtopossessanticanceractivitieswithverylowcytotoxicitytonormaltissue.Methodology/PrincipalFindings:Ourresultsfromcellviabilityassay,western-blotsandTdT-mediateddUT