Checkpoint Response and Platinum Drug Sensitivity

检查点反应和铂类药物敏感性

• 批准号: 7414869
• 负责人: ZAHID H SIDDIK
• 金额: $ 26.33万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-05-01 至 2012-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7414869
• 关键词: Address; Binding; Binding Sites; CDKN1A gene; Cell Cycle; Cell Cycle Checkpoint; Cell Cycle Deregulation; Cell Death; Cell Death Inhibition; Cell Line; Cell Survival; Cells; Cisplatin; Comparative Study; Complex; Cyclin D1; Cyclin E; Cyclin-Dependent Kinases; Cytotoxic agent; DNA Damage; Data; Drug effect disorder; Event; Failure; G1 Arrest; G1 Phase; G2 Phase; Gene Targeting; Goals; Knock-out; Knockout Mice; Link; Literature; Malignant Neoplasms; Mediating; Numbers; Ormaplatin; PCNA gene; Pathway interactions; Pharmaceutical Preparations; Phase; Platinum; Platinum Compounds; Process; Proliferating; Protein p53; Proteins; Proteomics; Recruitment Activity; Research Personnel; Resistance; Role; Satraplatin; Seminal; Signal Transduction; TP53 gene; Therapeutic; Therapeutic Agents; Transactivation; Tumor Cell Line; Tumor Suppressor Proteins; Up-Regulation; analog; antitumor agent; antitumor drug; base; cancer cell; concept; cytotoxic; design; diaminopyrimidine; dipeptidyl peptidase II; drug sensitivity; expression vector; improved; interest; molecular size; mutant; neoplastic cell; novel; oncoprotein p21; oxaliplatin; prevent; programs; response; size; stoichiometry; tumor

DESCRIPTION (provided by applicant): Although, by definition, cancer cells have a deregulated cell cycle, tumors often retain an intact G1 cell cycle checkpoint response via p53-dependent transactivation of p21, which then inhibits cyclin-dependent kinases (Cdk) and prevents G1/S transition. More importantly, tumors retaining this checkpoint response are also sensitive to therapeutic agents. Indeed, a strong positive correlation exists between the ability of tumor cells to arrest in G1 and sensitivity to platinum-based agents (cisplatin, tetraplatin and oxaliplatin) in the NCI 60- cell line tumor panel. This is also consistent with the finding that mutant-p53 tumor cells transfected with a p21 expression vector are sensitized to cisplatin. Moreover, our preliminary data demonstrate that p21- knockout induces resistance to cisplatin and to a novel analog DAP, which was designed to circumvent cisplatin resistance. The analog DAP is highly interesting among DNA-damaging agents in that it only inhibits G1-phase Cdk to selectively induce G1 arrest, and this consolidates the relationship between G1-phase Cdk inhibition by p21 and cell death. However, the underlying basis for this relationship has not been clearly defined in the literature, possibly due to signaling interference from the cross talk caused by inhibition of Cdk in S- and G2-phases, which are linked to cell-survival signaling. The availability of DAP, which does not inhibit the Cdk in these two phases, provides an important and timely opportunity to delineate this relationship so that rational approaches could emerge to improve the spectrum of therapeutic response. In preliminary studies, we have made a seminal observation that G1-phase Cdk complexes inhibited by DAP-induced p21 are substantially larger in size than the corresponding active complexes in control cells. Proteomic analysis of the inhibited complex identified the expected p21, but revealed PCNA as a novel recruit, which potentially links inhibition of G1-phase Cdk activity to platinum-mediated cell death. Therefore, we hypothesize that tumor cell death by platinum-based agents is dependent on p21 function at the G1-phase Cdk locus and this is facilitated by PCNA recruitment. We will address this hypothesis with three specific aims, which will better define our understanding of the process of G1-phase inhibition, and link this p21-dependent event to cell death. Moreover, comparative studies with platinum complexes will allow us to appreciate a mechanism of cisplatin resistance that is circumventable by non-cross-resistant analogs.

描述（由申请人提供）：尽管根据定义，癌细胞的细胞周期失调，但肿瘤通常通过p53依赖性p21保留完整的G1细胞周期检查点响应，然后抑制细胞周期蛋白依赖性激酶（CDK）并导致G1/S/s的过渡。更重要的是，保留此检查点反应的肿瘤也对治疗剂敏感。实际上，NCI 60-细胞系肿瘤面板中肿瘤细胞在G1中停滞的能力与对铂基剂（顺铂，四磷脂和奥沙利铂）的敏感性之间存在很强的阳性相关性。这也与发现用P21表达载体转染的突变体p53肿瘤细胞对顺铂敏感。此外，我们的初步数据表明，p21-敲除诱导对顺铂的耐药性和对新型的模拟DAP的抗性，该模拟DAP旨在规避顺铂的抗性。在DNA损害剂中，模拟DAP非常有趣，因为它仅抑制G1相CDK有选择地诱导G1停滞，并且这巩固了P21与细胞死亡抑制G1-相CDK之间的关系。但是，这种关系的基本基础尚未在文献中明确定义，这可能是由于抑制CDK在S-和G2倍方面引起的交叉谈话的信号干扰，这与细胞寿命的信号传导有关。 DAP的可用性不会抑制这两个阶段的CDK，它为描述这种关系提供了一个重要且及时的机会，以便可以出现理性方法以改善治疗反应的范围。在初步研究中，我们已经进行了开创性的观察，即DAP诱导的P21抑制的G1相CDK复合物的大小大大比对照细胞中的相应活性复合物大得多。对抑制复合物的蛋白质组学分析确定了预期的p21，但揭示了PCNA是一种新型募集，它可能将抑制G1相CDK活性与铂介导的细胞死亡联系起来。因此，我们假设基于铂的剂的肿瘤细胞死亡取决于G1期CDK基因座的p21功能，这是PCNA募集促进的。我们将以三个特定的目的来解决这一假设，这将更好地定义我们对G1期抑制过程的理解，并将这一依赖P21依赖性事件与细胞死亡联系起来。此外，对铂络合物的比较研究将使我们能够欣赏一种顺铂耐药性的机制，该机制可通过非交叉抗性的类似物来规避。