MITOCHONDRIA AND APOPTOSIS

这个子项目是利用资源的许多研究子项目之一。 由NIH/NCRR资助的中心拨款提供。对子项目的主要支持 子项目的首席调查员可能是由其他来源提供的， 包括美国国立卫生研究院的其他来源。为子项目列出的总成本可能 表示该子项目使用的中心基础设施的估计数量， 不是由NCRR赠款提供给次级项目或次级项目工作人员的直接资金。 以基因毒素为基础的DNA损伤剂和细胞周期抑制剂会对DNA造成巨大的损伤，激活检查点，并诱导几乎所有增殖细胞的凋亡。它们是癌症早期最有效的治疗方法。然而，随着癌症的发展，癌细胞积累了更多的突变，取消了检查点功能和凋亡程序，使它们对基于遗传毒素的治疗具有抗药性。最近开发的“靶向”疗法使用的是抑制特定基因或突变基因产物的药物，这些基因或突变基因产物的活性对特定类型癌症的发展和生长非常重要。一般来说，它们的毒性较小，但它们的影响可能非常戏剧性，在几天内缩小肿瘤。然而，有许多癌症在几年内以高度抵抗原始治疗的形式复发的事件。还有第三类化疗药物正在开发中。它们干扰癌细胞的高度糖酵解特性。大多数情况下，这些代谢抑制剂并不是作为单一的药物来杀死癌细胞，而是与经典的细胞周期抑制剂和DNA损伤剂联合使用。已经有许多尝试通过2-脱氧葡萄糖(2-DG)与标准化疗药物相结合来治疗癌症。然而，在大多数情况下，在标准化疗药物中添加2-DG的预期收益微乎其微，这表明2-DG诱导的信号和基因毒素诱导的信号不能协同工作。我们正在研究促凋亡蛋白与2-DG的结合以协同诱导癌细胞的凋亡。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Genotoxin-based DNA damaging agents and cell cycle inhibitors cause massive damage to DNA, activating checkpoints and inducing apoptosis in nearly all of the proliferating cells. They are the most effective therapies in early stages of cancer. However, as cancer progresses, cancer cells accumulate more mutations, abrogating checkpoints functions and apoptosis programs, making them resistant to genotoxin-based treatments. More recently developed "targeted" therapies use drugs that inhibit specific gene or mutated gene products whose activities are important in cancer development and growth in particular types of cancer. Generally they are less toxic, yet their effects can be very dramatic, shrinking tumors within days. However, there are numerous incidents of cancer returning within a few years, in forms highly resistant to the original therapy. There is a third group of chemotherapeutics being developed. They interfere with the highly glycolytic nature of cancer cells. Most of the time, these metabolic inhibitors are not used as a single agent to kill cancer cells, but instead, they are used in combination with the classic cell cycle inhibitors and DNA damaging agents. There have been many attempts to treat cancer by 2-deoxyglucose (2-DG) in combination with the standard chemotherapeutics. In most cases, however, hoped-for gains by adding 2-DG to the standard chemotherapeutics were marginal, suggesting that the 2-DG-induced signals and the genotoxin-induced signals do not work synergistically. We are investigating the combination of pro-apoptotic proteins with 2-DG to synergistically induce apoptosis in cancer cells.