Chemoprevention of Colorectal Cancer by Aldose Reductase Inhibition
通过抑制醛糖还原酶化学预防结直肠癌
基本信息
- 批准号:8196760
- 负责人:
- 金额:$ 30.39万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2007
- 资助国家:美国
- 起止时间:2007-12-01 至 2013-03-31
- 项目状态:已结题
- 来源:
- 关键词:AblationAddressAdenocarcinoma CellAffectAldehyde ReductaseAldehydesAntioxidantsAzoxymethaneBiochemicalCancer Cell GrowthCancer PatientCause of DeathCell ProliferationCell physiologyCellsCessation of lifeChemopreventionChemopreventive AgentChronicClinical ProtocolsClinical TrialsColon CarcinomaColorectal CancerColorectal NeoplasmsCultured CellsDataDevelopmentDiagnosisDinoprostoneDiseaseDoseEndotoxinsEnzymesEpidemiologic StudiesEventFibroblast Growth FactorFoundationsFunctional disorderFutureGenerationsGenesGlutathioneGoalsGrowthGrowth FactorHT29 CellsHealthHomeostasisHumanImplantInflammationInflammatoryInflammatory ResponseInjuryKnockout MiceLeadLightLipid PeroxidationLipidsLiverMalignant NeoplasmsMeasuresMediatingMediator of activation proteinMetabolicMetabolismMethodsModelingMolecularMolecular TargetMusNormal tissue morphologyNude MiceOxidantsOxidation-ReductionOxidative StressParticipantPathway interactionsPatientsPharmaceutical PreparationsPhosphorylationPlatelet-Derived Growth FactorPositioning AttributeProductionPropertyProtein DephosphorylationRNA InterferenceReactive Oxygen SpeciesRegulationResearchRiskRisk FactorsRoleSignal PathwaySignal TransductionSkinSpleenStagingStimulusTNF geneTestingTherapeuticTherapeutic UsesTissuesTranscription Factor AP-1WorkXenograft procedureactivating transcription factorbasecancer cellcarcinogenesiscellular targetingcolon cancer cell linecolon carcinogenesiscytokineexperiencein vivoinflammatory markerinhibitor/antagonistinnovationmacrophageneoplastic cellnovelpreventsorbiniltolrestattranscription factortumortumor growthtumor progressiontumorigenesistumorigenicupstream kinase
项目摘要
SUMMARY
Chronic inflammatory diseases and oxidative stress are major risk factors of colorectal cancer (CRC), the
second-ranked cause of death among cancer patients. However, the mechanisms through which increased
oxidative stress and inflammatory markers cause CRC are not well understood. Understanding these
biochemical mechanisms, especially the role of increased reactive oxygen species (ROS) in the
pathophysiology of CRC, will help in developing better therapeutic strategies. We have recently
demonstrated that aldose reductase (AR) an enzyme that we have shown catalyzes the reduction of ROS-
induced lipid aldehydes and their glutathione-conjugates (such as HNE and GS-HNE to DHN and GS-DHN),
is an obligatory mediator of growth factor and cytokine-induced NF-¿B activation in human colon cancer
cells. Further, we have shown that AR inhibition or ablation by SiRNA prevents the growth of colon cancer
cells in culture as well as in nude mice xenografts. Our long term goal is to understand the mechanisms by
which AR contributes to CRC progression, and to develop AR inhibitors (ARIs) for chemoprevention of CRC.
We will now systematically examine our hypothesis that the effects of ROS are in part mediated by AR-
catalyzed reduced lipid peroxidation-derived aldehydes (LDAs) and their metabolites by investigating the role
of AR in mediating growth factor-induced cancer growth in cultured cells, nude mice xenografts and murine
models of CRC. Our specific aims are 1) Investigate the effects of AR inhibition on the growth factor-induced
progression of cultured human colon cancer cell growth, 2) Delineate the effects of AR inhibition/ablation on
colon cancer progression in nude mouse xenografts, and 3) Delineate the chemopreventive efficacy of AR
inhibition in chemically and genetically-induced CRC in murine models. Completion of these studies should
identify the molecular mechanisms of AR- reduced LDAs in mediating carcinogenic signals, and lead to use
of AR inhibitors as excellent chemopreventive drugs for CRC.
摘要
慢性炎症性疾病和氧化应激是结直肠癌的主要危险因素,
在癌症患者中排名第二的死因。然而,通过这些机制增加了
氧化应激和炎症标记物导致结直肠癌的机制尚不清楚。了解这些
生化机制,特别是增加的活性氧(ROS)在体内的作用
结直肠癌的病理生理学研究将有助于制定更好的治疗策略。我们最近做了
证明了醛糖还原酶(AR),一种我们已经证明的酶,催化ROS的还原-
诱导脂醛及其谷胱甘肽偶联物(如HNE和GS-HNE到DHN和GS-DHN),
是生长因子和细胞因子诱导的人结肠癌核因子-βB活化的必备介质
细胞。此外,我们已经证明,通过siRNA抑制或消融AR可以防止结肠癌的生长。
培养的细胞以及裸鼠移植瘤中的细胞。我们的长期目标是通过
其中AR有助于CRC的进展,并开发AR抑制剂(ARI)用于化学预防CRC。
我们现在将系统地检验我们的假设,即ROS的影响部分是由AR-
催化还原脂质过氧化衍生醛及其代谢物的作用
AR在介导生长因子诱导的培养细胞、裸鼠移植瘤和小鼠肿瘤生长中的作用
CRC的模型。我们的具体目标是:1)研究AR抑制对生长因子诱导的细胞增殖的影响
培养的人结肠癌细胞生长的研究进展,2)AR抑制/消融对人结肠癌细胞生长的影响
结肠癌在裸鼠移植瘤中的进展,以及3)AR的化学预防效果
化学和遗传诱导的小鼠结直肠癌模型中的抑制。完成这些研究应
鉴定AR降低的LDAs在介导致癌信号中的分子机制,并引导使用
AR抑制剂是治疗结直肠癌的优良化学预防药物。
项目成果
期刊论文数量(0)
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{{ truncateString('SATISH K SRIVASTAVA', 18)}}的其他基金
Role of Aldose Reductase in Diabetic Complications
醛糖还原酶在糖尿病并发症中的作用
- 批准号:
8007485 - 财政年份:2009
- 资助金额:
$ 30.39万 - 项目类别:
Chemoprevention of Colorectal Cancer by Aldose Reductase Inhibition
通过抑制醛糖还原酶化学预防结直肠癌
- 批准号:
7535036 - 财政年份:2007
- 资助金额:
$ 30.39万 - 项目类别:
Chemoprevention of Colorectal Cancer by Aldose Reductase Inhibition
通过抑制醛糖还原酶化学预防结直肠癌
- 批准号:
8650276 - 财政年份:2007
- 资助金额:
$ 30.39万 - 项目类别:
Chemoprevention of Colorectal Cancer by Aldose Reductase Inhibition
通过抑制醛糖还原酶化学预防结直肠癌
- 批准号:
7738905 - 财政年份:2007
- 资助金额:
$ 30.39万 - 项目类别:
Chemoprevention of Colorectal Cancer by Aldose Reductase Inhibition
通过抑制醛糖还原酶化学预防结直肠癌
- 批准号:
7996629 - 财政年份:2007
- 资助金额:
$ 30.39万 - 项目类别:
Chemoprevention of Colorectal Cancer by Aldose Reductase Inhibition
通过抑制醛糖还原酶化学预防结直肠癌
- 批准号:
7373871 - 财政年份:2007
- 资助金额:
$ 30.39万 - 项目类别:
Chemoprevention of Colorectal Cancer by Aldose Reductase Inhibition
通过抑制醛糖还原酶化学预防结直肠癌
- 批准号:
8503346 - 财政年份:2007
- 资助金额:
$ 30.39万 - 项目类别:
Chemoprevention of Colorectal Cancer by Aldose Reductase Inhibition
通过抑制醛糖还原酶化学预防结直肠癌
- 批准号:
9038314 - 财政年份:2007
- 资助金额:
$ 30.39万 - 项目类别:
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