MITOCHONDRIA AND APOPTOSIS

这个子项目是许多利用资源的研究子项目之一 由NIH/NCRR资助的中心拨款提供。子项目的主要支持 而子项目的主要调查员可能是由其他来源提供的， 包括其它NIH来源。 列出的子项目总成本可能 代表子项目使用的中心基础设施的估计数量， 而不是由NCRR赠款提供给子项目或子项目工作人员的直接资金。 基于遗传毒素的DNA损伤剂和细胞周期抑制剂对DNA造成大规模损伤，激活检查点并在几乎所有增殖细胞中诱导凋亡。它们是癌症早期最有效的治疗方法。然而，随着癌症的进展，癌细胞积累更多的突变，废除检查点功能和凋亡程序，使它们对基于基因毒素的治疗产生抗性。 最近开发的“靶向”疗法使用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在特定类型的癌症的发展和生长中是重要的。一般来说，它们的毒性较小，但它们的效果可能非常显著，在几天内缩小肿瘤。然而，有许多癌症在几年内复发的事件，对原始疗法具有高度抗性。第三组化疗药物正在开发中。它们干扰癌细胞的高度糖酵解性质。大多数情况下，这些代谢抑制剂不是作为单一药物杀死癌细胞，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）与标准化疗药物组合来治疗癌症。然而，在大多数情况下，通过将2-DG添加到标准化疗药物中所希望的增益是边际的，这表明2-DG诱导的信号和基因毒素诱导的信号不协同工作。我们正在研究促凋亡蛋白与2-DG协同诱导癌细胞凋亡的组合。

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.