GLUCOSE-REGULATED STRESSES INDUCE RESISTANCE TO CAMPTOTHECIN IN HUMANCANCER-CELLS

The glucose-regulated stress response in mammalian cells is characteri zed by the increased synthesis of glucose-regulated proteins (GRPs). I n this study, we found that GRP-inducing conditions in culture led to induction of resistance to the topoisomerase I-targeted drug camptothe cin in human colon cancer HT-29 and ovarian cancer A2780 cells. The in duction of camptothecin resistance was accompanied by decreased levels of camptothecin-induced cleavable complexes, as measured by a topoiso merase I band depletion assay. However, topoisomerase I protein levels were the same in both stressed and non-stressed cells. Furthermore, w hen isolated nuclei from stressed and non-stressed cells were treated with camptothecin, similar levels of cleavable complexes were obtained , suggesting that the activity of topoisomerase I did not change in st ressed cells. In contrast, intracellular accumulation of camptothecin decreased in stressed cells. Our results indicate that stress-induced camptothecin resistance could be explained by reduced camptothecin acc umulation, leading to decreased numbers of cleavable complexes, withou t quantitative or qualitative changes in topoisomerase I levels. In ad dition, cell cycle analysis revealed that the GRP-inducing treatments resulted in an accumulation of G(1)/G(0)-phase cells. As camptothecin shows an S-phase-specific cytotoxicity, the G(1)/G(0)-phase accumulati on is another mechanism for camptothecin resistance. Since a glucose-r egulated response is produced by hypoxia and nutrient deprivation that occur naturally in solid tumors, the resistance observed here can occ ur in some solid tumors and can be an obstacle to chemotherapy. (C) 19 96 Wiley-Liss, Inc.