Oral Epigallocatechin Gallate (EGCG) for Treatment of Cisplatin Ototoxicity
口服表没食子儿茶素没食子酸酯(EGCG)治疗顺铂耳毒性
基本信息
- 批准号:10405612
- 负责人:
- 金额:$ 35.65万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2018
- 资助国家:美国
- 起止时间:2018-06-01 至 2025-05-31
- 项目状态:未结题
- 来源:
- 关键词:4 hydroxynonenalAcute Kidney FailureAdoptedAffectAldehydesAmifostineAminoglycoside AntibioticsAnti-Inflammatory AgentsAntineoplastic AgentsAntioxidantsApoptosisApoptoticApplications GrantsBindingBreast Cancer CellBuffersCancer PatientCarboplatinCardiovascular DiseasesCatechinCell CycleCell DeathCell SurvivalCellsCellular MembraneCentral Nervous System NeoplasmsChildChild DevelopmentChildhoodCisplatinCochleaCognitionColon CarcinomaComplementCouplesCysteineDNA AlkylationDataDevelopmentDiabetes MellitusDoseDose-LimitingDrug Side EffectsDrug TargetingEpigallocatechin GallateEquilibriumFutureGene Expression ProfilingGenerationsGenesGenetic TranscriptionGoalsGreen teaHair CellsHead and Neck CancerHumanHydroxyl RadicalIncidenceInflammationInflammatoryKnowledgeLinkLipid PeroxidationMalignant NeoplasmsMalignant neoplasm of ovaryMediatingMethionineMitogen-Activated Protein KinasesMutagensNADPH OxidaseNatural ProductsNeuraxisNeuroblastomaNeurodegenerative DisordersNeuropathyNoiseNon-Small-Cell Lung CarcinomaObesityOralOvarianOxidative StressPathway interactionsPatientsPharmaceutical PreparationsPhosphorylationPlatinumPopulationProcessProductionPropertyProtein IsoformsRattusReactive Oxygen SpeciesRegimenRoleSCID MiceSTAT1 proteinSTAT3 geneSerineSiteSmall Interfering RNASocial DevelopmentSolid NeoplasmSourceSpeechSulfhydryl CompoundsTP53 geneTherapeuticTherapeutic UsesTissue MicroarrayToxic effectXenograft procedureaminoglycoside-induced ototoxicityanti-cancerantioxidant therapybasecancer cellcancer therapycell killingchemotherapeutic agentchemotherapycisplatin induced hearing losseffective therapyeffectiveness testinghearing impairmenthearing loss treatmentimmunodeficient mouse modelimprovedinhibitorinterestknock-downmouse modelneoplastic cellnephrotoxicityneurotoxicitynovelotoprotectantototoxicityoxaliplatinrefractory cancerside effectsmall molecule inhibitorsodium thiosulfatestemtranscription factortranscriptome sequencingtreatment grouptreatment response
项目摘要
Cisplatin is a widely used chemotherapeutic agent for the treatment of a variety of human cancers. However, the
therapeutic benefits of this drug are compromised by dose limiting side effects such as ototoxicity, nephrotoxicity
and neurotoxicity. The incidence of cisplatin-induced hearing deficits, assessed by audiometric studies, range
from 75-100%. In the pediatric population, where cisplatin is used to treat neuroblastomas and central nervous
system malignancies, loss of hearing could hamper speech, cognition and social development of the child. Other
drugs, such as carboplatin and oxaliplatin, have emerged as alternatives to cisplatin, but their usefulness is
limited to a few cancers and they produce consistent neuropathies. Cisplatin is shown to be more effective than
carboplatin in treating non-small-cell lung cancer even though the side effects of the two drugs appear equivalent.
Thus, cisplatin still retains its importance as a component of the chemotherapeutic regimen for various cancers.
While the mechanism of chemotherapeutic efficacy of cisplatin appears to be DNA alkylation, the generation of
reactive oxygen species (ROS) via NOX3 NADPH oxidase appears critical for mediating cisplatin ototoxicity and
nephrotoxicity. This has stimulated interest for using antioxidants as otoprotectants. A limitation of this approach,
however, is that thiol-containing antioxidants could interfere with cisplatin antitumor efficacy. We have recently
shown that signal transducer and activator of transcription 1 (STAT1) couples ROS (from cisplatin) to the
inflammatory cascade, which exacerbates hearing loss. We also shown that knockdown of STAT1 (by siRNAs)
protects against cisplatin-induced hearing loss. Moreover, our preliminary data show that epigallocatechin gallate
(EGCG), the most abundant catechin in green tea and an inhibitor of STAT1 protects against cisplatin ototoxicity.
Interestingly, EGCG also activates STAT3, a transcription factor linked to cell survival. These dual mechanisms
of otoprotection by EGCG would be explored in more detail in this grant proposal. An added advantage of EGCG
is that it possesses intrinsic anticancer properties and does not interfere with cisplatin chemotherapeutic efficacy
in initial studies. The goals of this proposal are to determine the efficacy of oral EGCG against cisplatin
ototoxicity and nephrotoxicity in rats (Specific aims 1). The mechanisms underlying the protective action
of EGCG against cisplatin ototoxicity, focusing on the STAT1 and STAT3 pathways and gene expression
analysis, will be examined in Specific aim 2. Specific aim 3 will determine potential antitumor interference
by EGCG against different tumor cells in xenograft mouse models. The results provided in this study would
provide a better understanding of the utility of EGCG for the treatment of cisplatin oto- and nephrotoxicity and
could support its therapeutic use in cancer patients. Furthermore, this study should expand our knowledge
concerning the importance of STAT1/STAT3 balance in hair cell survival.
顺铂是一种广泛使用的化疗药物,用于治疗多种人类癌症。然而,
项目成果
期刊论文数量(12)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Strategies to reduce the risk of platinum containing antineoplastic drug-induced ototoxicity.
- DOI:10.1080/17425255.2020.1806235
- 发表时间:2020-10
- 期刊:
- 影响因子:4.3
- 作者:Mukherjea D;Dhukhwa A;Sapra A;Bhandari P;Woolford K;Franke J;Ramkumar V;Rybak L
- 通讯作者:Rybak L
Mechanisms of Cisplatin-Induced Ototoxicity and Otoprotection.
- DOI:10.3389/fncel.2017.00338
- 发表时间:2017
- 期刊:
- 影响因子:5.3
- 作者:Sheth S;Mukherjea D;Rybak LP;Ramkumar V
- 通讯作者:Ramkumar V
Ototoxicity of Non-aminoglycoside Antibiotics.
- DOI:10.3389/fneur.2021.652674
- 发表时间:2021
- 期刊:
- 影响因子:3.4
- 作者:Rybak LP;Ramkumar V;Mukherjea D
- 通讯作者:Mukherjea D
Regulator of G protein signaling 17 represents a novel target for treating cisplatin induced hearing loss.
G 蛋白信号调节器 17 是治疗顺铂诱导的听力损失的新靶点。
- DOI:10.1038/s41598-021-87387-5
- 发表时间:2021-04-14
- 期刊:
- 影响因子:4.6
- 作者:Dhukhwa A;Al Aameri RFH;Sheth S;Mukherjea D;Rybak L;Ramkumar V
- 通讯作者:Ramkumar V
Targeting CXCL1 chemokine signaling for treating cisplatin ototoxicity.
- DOI:10.3389/fimmu.2023.1125948
- 发表时间:2023
- 期刊:
- 影响因子:7.3
- 作者:
- 通讯作者:
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{{ truncateString('LEONARD P RYBAK', 18)}}的其他基金
ENDOGENOUS MODULATION OF OTOTOXICITY OF CISPLATIN
顺铂耳毒性的内源性调节
- 批准号:
2443624 - 财政年份:1994
- 资助金额:
$ 35.65万 - 项目类别:
ENDOGENOUS MODULATION OF OTOTOXICITY OF CISPLATIN
顺铂耳毒性的内源性调节
- 批准号:
2127726 - 财政年份:1994
- 资助金额:
$ 35.65万 - 项目类别:
ENDOGENOUS MODULATION OF OTOTOXICITY OF CISPLATIN
顺铂耳毒性的内源性调节
- 批准号:
2127728 - 财政年份:1994
- 资助金额:
$ 35.65万 - 项目类别:
ENDOGENOUS MODULATION OF OTOTOXICITY OF CISPLATIN
顺铂耳毒性的内源性调节
- 批准号:
2127727 - 财政年份:1994
- 资助金额:
$ 35.65万 - 项目类别:
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