Checkpoint Response and Platinum Drug Sensitivity

检查点反应和铂类药物敏感性

基本信息

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
项目类别：
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

项目摘要

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）：虽然根据定义，癌细胞具有失调的细胞周期，但肿瘤通常通过 p53 依赖性 p21 反式激活保留完整的 G1 细胞周期检查点反应，然后抑制细胞周期蛋白依赖性激酶 (Cdk) 并防止G1/S 过渡。更重要的是，保留这种检查点反应的肿瘤也对治疗药物敏感。事实上，在 NCI 60 细胞系肿瘤组中，肿瘤细胞停滞在 G1 期的能力与对铂类药物（顺铂、四铂和奥沙利铂）的敏感性之间存在很强的正相关性。这也与用p21表达载体转染的突变型p53肿瘤细胞对顺铂敏感的发现是一致的。此外，我们的初步数据表明，p21-敲除会诱导对顺铂和新型类似物 DAP 的耐药性，该类似物旨在规避顺铂耐药性。类似物 DAP 在 DNA 损伤剂中非常有趣，因为它仅抑制 G1 期 Cdk 以选择性诱导 G1 停滞，这巩固了 p21 抑制 G1 期 Cdk 与细胞死亡之间的关系。然而，这种关系的根本基础尚未在文献中明确定义，可能是由于 S 期和 G2 期 Cdk 抑制引起的串扰造成的信号干扰，而这与细胞生存信号相关。 DAP 在这两个阶段不会抑制 Cdk，它的出现为描述这种关系提供了一个重要且及时的机会，以便可以出现合理的方法来改善治疗反应范围。在初步研究中，我们进行了一项开创性的观察，即 DAP 诱导的 p21 抑制的 G1 期 Cdk 复合物的大小明显大于对照细胞中相应的活性复合物。对受抑制复合物的蛋白质组学分析鉴定出预期的 p21，但揭示 PCNA 是一种新的招募者，它可能将 G1 期 Cdk 活性的抑制与铂介导的细胞死亡联系起来。因此，我们假设铂类药物导致的肿瘤细胞死亡依赖于 G1 期 Cdk 位点的 p21 功能，而 PCNA 募集促进了这一过程。我们将通过三个具体目标来解决这一假设，这将更好地定义我们对 G1 期抑制过程的理解，并将这种 p21 依赖性事件与细胞死亡联系起来。此外，与铂络合物的比较研究将使我们了解顺铂耐药的机制，该机制可以通过非交叉耐药类似物来规避。