Project 2: Optimizing Redox Modulation as a Therapeutic Strategy for NHL

项目2： 三萜类化合物是一种新的亲电化合物，我们已经证明它能诱导细胞凋亡。 套细胞淋巴瘤(MCL)和弥漫性大细胞淋巴瘤(DLCL)。事实上，我们出版的和初步的 研究表明，这些化合物显示了它们的细胞毒性作用，既增加了 活性氧物种(ROS)，并降低这种关键的抗氧化防御机制的活性 硫氧还蛋白(Trx)和线粒体！蛋白水解酶、LON和CIPXP。这表明了一种新的治疗方法 基于调节淋巴瘤细胞氧化还原状态的淋巴瘤治疗策略。此外，我们建议的 机制表明，其他氧化还原活性物质，如蛋白酶体抑制剂和组蛋白脱乙酰酶 抑制剂，是与三萜类化合物结合的基本试剂。这项提案的具体目标有 以提供必要的临床前数据，以支持对 DLCL和MCL患者的最佳三萜类和其他氧化还原活性药物组合。 具体地说，在具体目标1中，我们将验证我们提出的三萜类化合物的活性机理，以便 体外优化三萜类药物组合。这些组合将进一步优化，并将 DLCL和DLCL体内验证ROS生成、TRX和线粒体蛋白酶的生物学靶点 特定靶点的MCL/SCID异种移植模型2.我们预计来自这些特定靶点的数据 将提出一种最佳的三萜类化合物组合，以及将在上下文中研究的给药顺序 具体目标3.本试验的一个关键组成部分是相关的 我们建议确定该药物组合对ROS、TRX的体内影响的实验室研究 淋巴瘤患者的线粒体蛋白水解酶活性。进一步预计，这些经验教训 从这些研究中学到的知识将支持我们的长期目标，即了解 非霍奇金淋巴瘤中的亲电化合物家族，其中还包括巴特烯内酯、葫芦素和 更重要的是，如何最好地利用淋巴瘤的氧化还原状态来产生新的和 治疗非霍奇金淋巴瘤的有效方法。

Project 2: The triterpenoids are novel electrophilic compounds that we have shown induce apoptotic cell death in mantle cell lymphoma (MCL) and diffuse large cell lymphoma (DLCL). Indeed our published and preliminary studies suggest that these compounds manifest their cytotoxic effects by both increasing the generation of reactive oxygen species (ROS), and decreasing the activity of such critical anti-oxidant defense mechanisms as thioredoxin (Trx) and the mitochondria! proteases, Lon and CIpXP. This suggests a novel therapeutic strategy for lymphoma based on modulating the lymphoma cell redox state. In addition, our proposed mechanism suggests that other redox active agents, such as proteosome inhibitors and histone deacetylase inhibitors, are rationale agents to combine with the triterpenoids. The Specific Aims of this proposal have been developed to provide the essential pre-clinical data needed to support the clinical evaluation of the optimal triterpenoid and other redox active agent combinations for patients with DLCL and MCL. Specifically, in Specific Aim 1, we will validate our proposed mechanism of activity of the triterpenoids so to optimize triterpenoid drug combinations in vitro. These combinations will be further optimized and the biological targets of ROS generation, Trx and mitochondrial proteases validated in vivo using DLCL and MCL/SCID xenograft models in Specific Aim 2. We anticipate that the data derived from these Specific Aims will suggest an optimal triterpenoid combination, and sequence of drug delivery to be studied in the context of a phase l/ll trial as proposed in Specific Aim 3. A critical component of this trial will be the correlative laboratory studies whereby we propose to determine the in vivo effects of this drug combination on ROS, Trx and mitochondrial protease activity in patients with lymphoma. It is further anticipated that the lessons learned from these studies will support our long term goals which are to understand the clinical potential of the family of electrophilic compounds in NHL, which also includes the parthenolides, cucurmin, and the acivicins, and more importantly how best to exploit the redox state of lymphoma to generate new and effective approaches for the treatment of patients with NHL.