Abstract LB-162: DNA-damage foci persistence and accelerated senescence as determinants of radiosensitization by glycolysis inhibitors

Abstract

Abstract One of the most striking characteristics of cancer cells is their altered glucose metabolism. Many cancer cells display a dramatic elevation in glucose utilization, independent of the availability of oxygen or the activity of oxidative phosphorylation. Cancers often display the Warburg effect, wherein glycolysis drives fermentation of pyruvate to lactate even under aerobic conditions. Aerobic glycolysis has been widely investigated and it is now considered a metabolic hallmark of transformation and a key driver for cancer cell proliferation, malignancy, metastasis, and therapeutic resistance. En route to cancer, pre-malignant cancer cells have to overcome cellular senescence which is recognized as a barrier for tumorigenesis. Recent data link both replicative and accelerated senescence to persistent DNA damage signals that arise from domains of modified chromatin at sites of un-repairable double strand breaks. Our prior work has established the kinetics of resolution of these chromatin domains, dubbed ionizing radiation induced foci (IRIF), and resulting effects on accelerated senescence as determinants of radiation sensitivity and as a target that can sensitize cancer cells to genotoxic therapy. To obtain probes that impinge on the DNA damage response and senescence, we developed a cell based assay for high throughput, high content screening based on the detection of IRIF persistence. Screening over 2500 drugs, including natural products and drug-like compounds identified known DNA damaging agents as well as novel candidates. To gain mechanistic insight, we tested these “hits” in combination with the mitochondrial inhibitor antimycin A and discovered several that blocked ATP synthesis. Combining bona fide glycolytic pathway inhibitors with radiation enhanced IRIF persistence and accelerated senescence in vitro. The glucokinase inhibitor 2-DG increased IRIF persistence and senescence after irradiation of tumor xenografts. These data suggest a critical role for aerobic glycolysis in the proliferation and survival of cancer cells to prevent stress-induced premature senescence, specifically by blocking the formation of DNA damage foci and/or preventing their persistence. Rather than simply satisfying energy needs, aerobic glycolysis likely serves an important survival and immortalization function for cancer cells. As such, targeting the Warburg effect to promote cancer cell senescence appears to be an attractive strategy for therapeutic intervention, particularly in combination with genotoxic therapy. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-162. doi:1538-7445.AM2012-LB-162