MITOCHONDRIA AND APOPTOSIS

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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.