Mitochondria-targeted Agents in Breast Cancer
乳腺癌中的线粒体靶向药物
基本信息
- 批准号:8271285
- 负责人:
- 金额:$ 30.59万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2010
- 资助国家:美国
- 起止时间:2010-06-14 至 2015-04-30
- 项目状态:已结题
- 来源:
- 关键词:ABCB1 geneAcetylcysteineAdenovirusesAdjuvantAdjuvant ChemotherapyAdjuvant TherapyAdultAdverse effectsAnimal ModelAnthracenesAnthracyclinesAntibioticsAntioxidantsApoptosisAttenuatedBiological AssayBreastBreast Cancer CellBreast Cancer Early DetectionBreast Cancer ModelBreast Cancer TreatmentBreast CarcinomaCardiacCardiac MyocytesCardiomyopathiesCardiotoxicityCardiovascular DiseasesCationsCell ProliferationCell SurvivalCellsChelating AgentsChemotherapy-Oncologic ProcedureClinicalCoupledDNA FragmentationDetectionDoseDoxorubicinEchocardiographyEnzymesEpithelial CellsFluorescenceGene TransferGenerationsGlycogen Branching EnzymeGoalsHigh Pressure Liquid ChromatographyHodgkin DiseaseImageImaging TechniquesIronLabelLeadLinkMCF7 cellMammary NeoplasmsMammary glandMeasuresMediatingMethylnitrosoureaMitochondriaModelingMonitorMulti-Drug ResistanceMyocardialMyocardiumNeurodegenerative DisordersNon-MalignantOrganOxidative StressP-GlycoproteinPatientsPharmaceutical PreparationsProteinsQuinonesRattusReactive Oxygen SpeciesReportingResearchRespiratory ChainTechnetiumTechniquesTestingThymidineToxic effectTreatment EfficacyUbiquinoneUp-RegulationVitamin EWestern BlottingWorkanalogantioxidant therapyantitumor agentbasechemotherapeutic agentchemotherapyclinically relevantcombatcyclooxygenase 2cytotoxiccytotoxicitydimethylbenzanthraceneduramycinimaging modalityimaging probeimprovedin vivoinnovationleukemiamalignant breast neoplasmmimeticsnoveloverexpressionpre-clinicalresearch studyresponsesuccesstempoltumortumor growthuptake
项目摘要
ABSTRACT
We will develop mitochondria-targeted antioxidants (MTAs) and imaging probes that will mitigate cardiotoxicity
and enhance antitumor efficacies of chemotherapeutic drugs. We will use doxorubicin (DOX), a front-line
antitumor agent in breast cancer treatment. DOX causes delayed dose-dependent cardiotoxicity. Clinically,
this side effect is managed with conventional antioxidants and iron chelators. This proposal provides a new
adjuvant approach in breast cancer chemotherapy. Its genesis is based upon the following discoveries: 1)
MTAs (e.g., Mito-Q, a synthetic drug analog of an endogenous antioxidant, Co-enzyme-Q, present in the
mitochondrial respiratory chain) inhibit DOX-mediated cardiotoxicity in a preclinical animal model and in
cardiomyocytes, and 2) MTAs (Mito-Q and Mito-CP, a nitroxide targeted to mitochondria) cause
antiproliferative and cytotoxic effects in breast cancer cells (MCF-7 and MDA-MB-231) but not in non-
transformed breast epithelial cells (MCF-10A) and significantly enhance DOX-induced breast cancer cell
toxicity. We hypothesize that mitochondria-targeted antioxidants enhance DOX-mediated antitumor
effects but attenuate DOX cardiotoxicity. Response to chemotherapy will be monitored by using the
mitochondria-targeted technetium-labeled imaging agents (99mTc-Mito10-MAG3) in a chemically-induced breast
carcinoma animal model. Specifically, we will: (i) Investigate the cytotoxic effects of MTAs alone and with DOX
in breast cancer cells, (ii) Assess the cytotoxic effects of MTAs and DOX in breast cancer cells overexpressing
multi-drug resistant protein, (iii) Evaluate the adjuvant chemotherapeutic effects of MTAs and DOX in an in vivo
breast cancer model, and (iv) Assess the cardioprotective and oxy-radical scavenging effects of MTAs in DOX-
treated cardiomyocytes and in DOX-treated rat cardiomyopathy model. These aims will be accomplished
using HPLC-fluorescence and HPLC-electrochemical detection techniques, scintimammography and
echocardiography. Abnormal generation of reactive oxygen species will be detected using novel species- and
target-specific probes. We will develop innovative MTA-based adjuvant therapy that can be used to inhibit
DOX-induced cardiotoxicity. This research may potentially lead to novel ways for improving the therapeutic
efficacy of DOX and other antitumor agents used in breast cancer treatment.
摘要
我们将开发靶向抗氧化剂(MTA)和成像探针,以减轻心脏毒性
增强化疗药物的抗肿瘤功效。我们将使用多柔比星(DOX),
在乳腺癌治疗中的抗肿瘤剂。DOX引起延迟的剂量依赖性心脏毒性。在临床上,
这种副作用可以用常规的抗氧化剂和铁螯合剂来控制。该提案提供了一个新的
乳腺癌化疗的辅助方法。它的起源基于以下发现:1)
MTA(例如,Mito-Q是一种内源性抗氧化剂辅酶Q的合成药物类似物,存在于
线粒体呼吸链)在临床前动物模型中抑制DOX介导的心脏毒性,
2)MTA(Mito-Q和Mito-CP,一种靶向线粒体的氮氧自由基)引起
在乳腺癌细胞(MCF-7和MDA-MB-231)中的抗增殖和细胞毒性作用,但在非乳腺癌细胞中没有。
转化的乳腺上皮细胞(MCF-10A),并显著增强DOX诱导的乳腺癌细胞
毒性我们假设靶向抗氧化剂能增强DOX介导的抗肿瘤作用。
但减弱DOX心脏毒性。将通过使用
化学诱导乳腺癌中的靶向锝标记显像剂(99 mTc-Mito 10-MAG 3)
肿瘤动物模型。具体地说,我们将:(i)研究单独的MTA和DOX的细胞毒性作用
(ii)评估MTA和DOX在乳腺癌细胞中的细胞毒性作用,
多药耐药蛋白,(iii)评估MTA和DOX在体内的辅助化疗效果
乳腺癌模型,和(iv)评估在DOX-1中MTA的心脏保护和氧自由基清除作用。
治疗的心肌细胞和DOX治疗的大鼠心肌病模型。这些目标将会实现
使用HPLC-荧光和HPLC-电化学检测技术,
超声心动图活性氧物质的异常产生将使用新的物质来检测,
目标特异性探针。我们将开发创新的基于MTA的辅助治疗,
DOX诱导的心脏毒性。这项研究可能会导致新的方法来改善治疗
DOX和其他抗肿瘤药物在乳腺癌治疗中的疗效。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
数据更新时间:{{ journalArticles.updateTime }}
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
BALARAMAN KALYANARAMAN其他文献
BALARAMAN KALYANARAMAN的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ truncateString('BALARAMAN KALYANARAMAN', 18)}}的其他基金
Chemoprevention of lung cancer by targeting lonidamine to mitochondria
通过将氯尼达明靶向线粒体来化学预防肺癌
- 批准号:
9763831 - 财政年份:2019
- 资助金额:
$ 30.59万 - 项目类别:
Chemoprevention of lung cancer by targeting lonidamine to mitochondria
通过将氯尼达明靶向线粒体来化学预防肺癌
- 批准号:
9915863 - 财政年份:2019
- 资助金额:
$ 30.59万 - 项目类别:
Chemoprevention of lung cancer by targeting lonidamine to mitochondria
通过将氯尼达明靶向线粒体来化学预防肺癌
- 批准号:
10489835 - 财政年份:2019
- 资助金额:
$ 30.59万 - 项目类别:
Chemoprevention of lung cancer by targeting lonidamine to mitochondria
通过将氯尼达明靶向线粒体来化学预防肺癌
- 批准号:
10476701 - 财政年份:2019
- 资助金额:
$ 30.59万 - 项目类别:
Chemoprevention of lung cancer by targeting lonidamine to mitochondria
通过将氯尼达明靶向线粒体来化学预防肺癌
- 批准号:
10687020 - 财政年份:2019
- 资助金额:
$ 30.59万 - 项目类别:
Chemoprevention of Lung Cancer with Mitochondria-Targeted Honokiol
利用线粒体靶向和厚朴酚化学预防肺癌
- 批准号:
10497449 - 财政年份:2017
- 资助金额:
$ 30.59万 - 项目类别:
Chemoprevention of lung cancer with mitochondria-targeted honokiol
线粒体靶向和厚朴酚对肺癌的化学预防
- 批准号:
10092125 - 财政年份:2017
- 资助金额:
$ 30.59万 - 项目类别:
相似海外基金
抗酸化能を高めたN-acetylcysteineによる老視と白内障抑制機構の解明
阐明具有增强抗氧化能力的N-乙酰半胱氨酸抑制老花眼和白内障的机制
- 批准号:
23K15945 - 财政年份:2023
- 资助金额:
$ 30.59万 - 项目类别:
Grant-in-Aid for Early-Career Scientists
Targeting the neurobiology of restricted and repetitive behaviors in children with autism using N-acetylcysteine
使用 N-乙酰半胱氨酸针对自闭症儿童限制性和重复性行为的神经生物学
- 批准号:
10758985 - 财政年份:2023
- 资助金额:
$ 30.59万 - 项目类别:
Targeting the neurobiology of restricted and repetitive behaviors in children with autism using N-acetylcysteine
使用 N-乙酰半胱氨酸针对自闭症儿童限制性和重复性行为的神经生物学
- 批准号:
10619173 - 财政年份:2022
- 资助金额:
$ 30.59万 - 项目类别:
High dose acetaminophen with n-acetylcysteine rescue as a novel STAT3 inhibitor with anti-cancer stem cell properties
高剂量对乙酰氨基酚与 n-乙酰半胱氨酸救援作为具有抗癌干细胞特性的新型 STAT3 抑制剂
- 批准号:
10517287 - 财政年份:2021
- 资助金额:
$ 30.59万 - 项目类别:
A randomised controlled trial of N-acetylcysteine for the treatment of alcohol use disorder
N-乙酰半胱氨酸治疗酒精使用障碍的随机对照试验
- 批准号:
nhmrc : 2001375 - 财政年份:2021
- 资助金额:
$ 30.59万 - 项目类别:
Clinical Trials and Cohort Studies Grants
High dose acetaminophen with n-acetylcysteine rescue as a novel STAT3 inhibitor with anti-cancer stem cell properties
高剂量对乙酰氨基酚与 n-乙酰半胱氨酸救援作为具有抗癌干细胞特性的新型 STAT3 抑制剂
- 批准号:
10368472 - 财政年份:2021
- 资助金额:
$ 30.59万 - 项目类别:
Targeting the neurobiology of restricted and repetitive behaviors in children with autism using N-acetylcysteine
使用 N-乙酰半胱氨酸针对自闭症儿童限制性和重复性行为的神经生物学
- 批准号:
10221760 - 财政年份:2020
- 资助金额:
$ 30.59万 - 项目类别:
N-acetylcysteineの骨治癒促進効果の検討
N-乙酰半胱氨酸促进骨愈合作用的考察
- 批准号:
20H01118 - 财政年份:2020
- 资助金额:
$ 30.59万 - 项目类别:
Grant-in-Aid for Encouragement of Scientists