Berberine downregulates MDM2 by interaction with DAXX in cancer cells
小檗碱通过与癌细胞中的 DAXX 相互作用下调 MDM2
基本信息
- 批准号:8010178
- 负责人:
- 金额:$ 31.2万
- 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:2010-01-01 至 2014-12-31
- 项目状态:已结题
- 来源:
- 关键词:Acute Lymphocytic LeukemiaAddressAlkaloidsApoptosisApoptoticBerberineBiological FactorsCancer Cell GrowthCancer PatientCellsChildhoodChinese PeopleClinicalClinical TrialsDAXX geneDataDevelopmentDown-RegulationDoxorubicinDrug resistanceFutureGoalsHealthHumanIsoquinolinesKnowledgeMDM2 geneMalignant Childhood NeoplasmMalignant NeoplasmsMedicinal HerbsMolecularNeuroblastomaOncogene ProteinsPathway interactionsPatientsPharmaceutical PreparationsPlayProtein p53ReagentRefractoryRegulationResistanceRoleTestingTherapeuticTherapeutic AgentsUbiquitinationUp-Regulationanticancer activitybasecancer cellcancer initiationcytotoxiccytotoxicitydesigndrug candidatedrug developmentin vivoinnovationkillingsnovel therapeuticsoutcome forecastoverexpressionpatient populationresponsetherapy resistantubiquitin-protein ligase
项目摘要
DESCRIPTION (provided by applicant): The multifunctional oncoprotein MDM2 plays critical roles in cancer initiation, progression and the development of resistance to therapy. We studied pediatric cancer patients, including those with acute lymphoblastic leukemia (ALL) and neuroblastoma (NB), finding that patients with a poor prognosis commonly had cancer cells that expressed constitutively high levels of MDM2. An important function of MDM2 is the ubiquitination (as an E3 ligase) and degradation of the tumor suppressor p53, due to interactions with DAXX and HAUSP. Interestingly, disruption of these interactions can result in self-ubiquitination of MDM2 and p53 activation. Thus, we believe targeting MDM2 by disrupting MDM2-DAXX-HAUSP interactions is an innovative approach to develop new therapeutics for MDM2-overexpressing cancer patients. Berberine (BBR), an isoquinoline alkaloid derived from a traditional Chinese medicinal herb, has been shown to have anti-proliferative and pro-apoptotic effects on human cancer. Our preliminary data supports a previously unrecognized mechanism of action for BBR: It downregulates MDM2 by inhibiting DAXX, disrupting MDM2-DAXX-HAUSP interactions. In contrast to the conventional chemotherapeutic drug doxorubicin (Dox) that induces prior p53 activation and a subsequent upregulation of MDM2, we discovered that BBR strongly induced persistent downregulation of MDM2, followed by a steady-state activation of p53, resulting in potent apoptosis of MDM2-overexpressing cancer cells, including those that are Dox-resistant. This proposal is designed to test our central hypothesis that regulation of MDM2 by DAXX inhibition is the major mechanism by which BBR differs from Dox in exerting its anti-cancer effect. The project's long term objectives are: characterization of the critical role BBR plays in the downregulation of MDM2 to overcome chemoresistance and determination of BBR's potential as a therapeutic reagent for refractory cancer patients. The specific aims of this study are: 1) To fully elucidate the cellular/molecular mechanisms by which BBR downregulates MDM2; 2) To establish that downregulation of MDM2 is the primary mechanism by which BBR exerts its anticancer effects; and 3) To assess the ability of BBR to reverse chemoresistance and its potential as a treatment for refractory cancer patients. Successful completion of these specific aims will generate knowledge with respect to the mechanisms of action for BBR prior to future clinical trials of this natural product in pediatric cancer patients, should introduce BBR as a highly useful new drug candidate for overcoming chemoresistance, and also will provide a basic framework for the rational design of other therapeutic approaches targeting the DAXX-MDM2 pathway. PUBLIC HEALTH RELEVANCE: We have found that BBR specifically and strongly inhibits MDM2 expression and induces activation of p53, which results in potent apoptosis of wt-p53/MDM2-overexpressing cancer cells, including those that were resistant to a conventional chemotherapeutic drug. In this study, we will elucidate the molecular mechanism by which BBR downregulates MDM2, which we have reason to believe involves inhibition of DAXX and eventual initiation of apoptosis through a previously unutilized drug development corridor. Importantly, we will investigate whether the natural product BBR could be used as an effective therapeutic reagent in the treatment of pediatric and refractory cancer patient populations.
描述(由申请人提供):多功能癌蛋白MDM2在癌症的发生、进展和治疗耐药性的发展中发挥着关键作用。我们研究了儿童癌症患者,包括患有急性淋巴细胞白血病 (ALL) 和神经母细胞瘤 (NB) 的患者,发现预后不良的患者通常具有表达高水平 MDM2 的癌细胞。 MDM2 的一个重要功能是由于与 DAXX 和 HAUSP 的相互作用而泛素化(作为 E3 连接酶)和肿瘤抑制因子 p53 的降解。有趣的是,这些相互作用的破坏可能导致 MDM2 和 p53 激活的自我泛素化。因此,我们相信通过破坏 MDM2-DAXX-HAUSP 相互作用来靶向 MDM2 是为 MDM2 过表达癌症患者开发新疗法的创新方法。小檗碱 (BBR) 是一种从传统中草药中提取的异喹啉生物碱,已被证明对人类癌症具有抗增殖和促凋亡作用。我们的初步数据支持了 BBR 以前未被认识的作用机制:它通过抑制 DAXX、破坏 MDM2-DAXX-HAUSP 相互作用来下调 MDM2。与传统化疗药物阿霉素(Dox)诱导p53激活和随后MDM2上调相反,我们发现BBR强烈诱导MDM2持续下调,随后p53稳态激活,导致MDM2过表达癌细胞(包括那些对Dox耐药的癌细胞)有效凋亡。该提案旨在检验我们的中心假设,即通过 DAXX 抑制调节 MDM2 是 BBR 与 Dox 发挥抗癌作用的主要机制。该项目的长期目标是:表征 BBR 在下调 MDM2 以克服化疗耐药性方面所发挥的关键作用,并确定 BBR 作为难治性癌症患者治疗试剂的潜力。本研究的具体目的是:1)全面阐明BBR下调MDM2的细胞/分子机制; 2) 确立MDM2的下调是BBR发挥抗癌作用的主要机制; 3) 评估 BBR 逆转化疗耐药的能力及其作为难治性癌症患者治疗的潜力。成功完成这些具体目标将在未来对该天然产物在儿科癌症患者中进行临床试验之前产生有关 BBR 作用机制的知识,应将 BBR 作为克服化疗耐药性的非常有用的新候选药物,并且还将为合理设计其他针对 DAXX-MDM2 途径的治疗方法提供基本框架。公共健康相关性:我们发现 BBR 特异性且强烈地抑制 MDM2 表达并诱导 p53 激活,从而导致 wt-p53/MDM2 过表达的癌细胞(包括那些对传统化疗药物产生耐药性的癌细胞)发生有效凋亡。在这项研究中,我们将阐明 BBR 下调 MDM2 的分子机制,我们有理由相信这涉及抑制 DAXX 并通过先前未利用的药物开发走廊最终启动细胞凋亡。重要的是,我们将研究天然产物 BBR 是否可以用作治疗儿童和难治性癌症患者群体的有效治疗试剂。
项目成果
期刊论文数量(0)
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MUXIANG ZHOU其他文献
MUXIANG ZHOU的其他文献
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{{ truncateString('MUXIANG ZHOU', 18)}}的其他基金
Berberine downregulates MDM2 by interaction with DAXX in cancer cells
小檗碱通过与癌细胞中的 DAXX 相互作用下调 MDM2
- 批准号:
8823737 - 财政年份:2010
- 资助金额:
$ 31.2万 - 项目类别:
Berberine downregulates MDM2 by interaction with DAXX in cancer cells
小檗碱通过与癌细胞中的 DAXX 相互作用下调 MDM2
- 批准号:
7766637 - 财政年份:2010
- 资助金额:
$ 31.2万 - 项目类别:
Berberine downregulates MDM2 by interaction with DAXX in cancer cells
小檗碱通过与癌细胞中的 DAXX 相互作用下调 MDM2
- 批准号:
8599444 - 财政年份:2010
- 资助金额:
$ 31.2万 - 项目类别:
Berberine downregulates MDM2 by interaction with DAXX in cancer cells
小檗碱通过与癌细胞中的 DAXX 相互作用下调 MDM2
- 批准号:
8204584 - 财政年份:2010
- 资助金额:
$ 31.2万 - 项目类别:
Berberine downregulates MDM2 by interaction with DAXX in cancer cells
小檗碱通过与癌细胞中的 DAXX 相互作用下调 MDM2
- 批准号:
8403808 - 财政年份:2010
- 资助金额:
$ 31.2万 - 项目类别:
Regulation of MDM2 auto-ubiquitination and molecular targeting
MDM2 自动泛素化和分子靶向的调控
- 批准号:
8503289 - 财政年份:2007
- 资助金额:
$ 31.2万 - 项目类别:
MDM2 regulates XIAP gene expression in cancer treatment
MDM2 在癌症治疗中调节 XIAP 基因表达
- 批准号:
7372276 - 财政年份:2007
- 资助金额:
$ 31.2万 - 项目类别:
MDM2 regulates XIAP gene expression in cancer treatment
MDM2 在癌症治疗中调节 XIAP 基因表达
- 批准号:
7541424 - 财政年份:2007
- 资助金额:
$ 31.2万 - 项目类别:
Regulation of MDM2 auto-ubiquitination and molecular targeting
MDM2 自动泛素化和分子靶向的调控
- 批准号:
8629704 - 财政年份:2007
- 资助金额:
$ 31.2万 - 项目类别:
MDM2 regulates XIAP gene expression in cancer treatment
MDM2 在癌症治疗中调节 XIAP 基因表达
- 批准号:
7993541 - 财政年份:2007
- 资助金额:
$ 31.2万 - 项目类别:
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