Thioredoxin Inhibition of Apoptosis and Cancer Treatment

抵抗正常调节的细胞死亡(细胞凋亡)是癌症表型的特征之一。 逃脱凋亡使癌细胞在低氧、高酸度和有限的条件下生长 在正常细胞无法存活的生长中的肿瘤中，可以发现营养物质的供应。它还解释了 癌细胞对放射和化疗的内在抵抗力。通过以下方式了解这些机制 哪些癌细胞变得对凋亡具有抵抗力是开发新的治疗方法的核心 癌症的治疗和克服抗药性。硫氧还蛋白(Trxs)是一种小的氧化还原蛋白， 通过黄素蛋白硫氧还蛋白还原酶进行可逆的NADPH依赖的还原。有两个 人Trxs、胞质Trx-1和线粒体Trx-2。TRX-1转化正常细胞，刺激细胞 多种抗癌药物对肿瘤细胞的生长和细胞凋亡有明显的抵抗作用。TRX-1基因过度表达 在许多与侵袭性肿瘤生长相关的人类原发肿瘤中，自发性降低 细胞凋亡和患者生存期减少。Trx-I抑制细胞凋亡的机制(S)不是 为人所知。我们已经证明TRX-1与肿瘤抑制蛋白PTEN结合并抑制其活性， 磷脂酰肌醇-3-激酶/Akt细胞生存信号通路的脂质磷酸酶抑制物。TRX-1 也会减少Noxa的表达，Noxa是P53依赖的细胞凋亡的调节因子。我们提出了新的证据 Trx-2保护线粒体免受氧化损伤，并可能保护癌细胞免受线粒体损伤 介导的细胞凋亡。提出的研究所基于的假设是，Trxs扮演着关键的角色 在阻止癌细胞凋亡中的作用；磷脂酰肌醇-3-激酶/Akt失活Trx-1 细胞存活途径和P53介导的细胞凋亡；以及保护TRX-2免受线粒体损伤。 此外，我们认为Trx的诱导物将阻断这些抗凋亡作用，并将是有效的。 抗肿瘤药物。我们将使用TRX-1抑制剂PX-12和我们已经确定的两种新型TRX-1抑制剂。 本研究的目的是探讨Trx抑制细胞凋亡的机制，并开发新的 我们已经确定TRX的抑制剂是治疗癌症的潜在药物。 城市、州)

Resistance to normal regulated cell death (apoptosis) is one of the characteristics of the cancer phenotype. Escape from apoptosis allows cancer cells to grow under conditions of low oxygen, high acidity and limited nutrient supply such as are found in the growing tumor where normal cells cannot survive. It also explains the intrinsic resistance of cancer cells to radiation and chemotherapy. Understanding the mechanisms by which cancer cells become resistant to apoptosis is central to the development of new therapies for the treatment of cancer and for overcoming drug resistance. Thioredoxins (Trxs) are small redox proteins that undergoes reversible NADPH- dependent reduction by flavoprotein thioredoxin reductases. There are two human Trxs, a cytosolic Trx-1 and a mitochondrial Trx-2. Trx-1 transforms normal cells, stimulates cell growth and causes a marked resistance to apoptosis by a variety of anticancer drugs. Trx-1 is over expressed in many human primary tumors where it is associated with aggressive tumor growth, decreased spontaneous apoptosis and with decreased patient survival. The mechanism(s) by which Trx-I inhibits apoptosis is not known. We have shown that Trx-1 binds to and represses the activity of the tumor suppresser protein PTEN, a lipid phosphatase inhibitor of the phosphatidyinositol-3-kinase/Akt cell survival signaling pathway. Trx-1 also decreases the expression ofNoxa a regulator ofp53-dependent apoptosis. We present new evidence that Trx-2 protects mitochondria against oxidant damage and may protect cancer cells against mitochondrial mediated apoptosis. The hypothesis upon which the proposed studies are based is that the Trxs play a critical role in preventing apoptosis in cancer cells; Trx-1 by inactivation of the phosphatidyinositol-3-kinase/Akt cell survival pathway and p53-mediated apoptosis; and Trx-2 by protection against mitochondrial damage. Furthermore, we propose that inl_bitors of Trx will block these antiapoptotic effects and will be effective antitumor agents. We will use the Trx-1 inhibitor PX-12 and two novel Trx-1 inhibitors we have identified. The objective of our studies is to investigate mechanisms for Trx inhibition of apoptosis and develop novel inhibitors of Trx we have identified as potential agents for the treatment of cancer. city, state)