Adriamycin is a cytotoxic drug used in the treatment of cancer and provokes a wide variety of actions on cells, including responses in the nucleus, the cytoplasm, the plasma membrane, and the signaling pathways between these loci. One well studied mechanism is the ability of the drug to stabilize the topo II/DNA complex, which is recognized by the cell as abnormal, leading to growth arrest and eventual cell death. The topo II action of the drug alone is not sufficient to commit the cells to cytotoxicity. The investigator has shown this to be the case in experiments where cells are manipulated to have high internal drug levels with none on the exterior. Although the drug-DNA-topoII interaction occurs, cell death is absent. However, when the drug is also present on the exterior where it can disrupt membrane signaling events, then apoptosis occurs. Brefeldin A, which also prevents protein processing and trafficking through the Golgi apparatus, also blocks adriamycin-induced apoptosis without preventing the topo II-drug-DNA cleavable complex. These data, in addition to data on low temperature studies with adriamycin, implicate cellular trafficking mechanisms as potential regulators of adriamycin induced apoptosis. The three specific aims of the application are 1) to examine the mechanistic implications of protection from adriamycin-induced cytotoxicity by Brefeldin A and low temperature by determining if intracellular protein trafficking pathways facilitate the cytotoxic effects of adriamycin and determining if adriamycin treatment modifies trafficking through the Golgi and endoplasmic reticulum; 2) to determine whether the induction of GRPs (glucose-regulated proteins) is directly related to the cytotoxic activity of adriamycin; and 3) to determine if the intracellular spatial distribution of p53 is linked to the action of adriamycin.
| Vichi, P J; Tritton, T R (1993) Protection from adriamycin cytotoxicity in L1210 cells by brefeldin A. Cancer Res 53:5237-43 |
