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
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)
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BALARAMAN KALYANARAMAN其他文献
BALARAMAN KALYANARAMAN的其他文献
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{{ 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:
10687020 - 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 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:
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