Adaphostin cytoxicity in glioblastoma cells is ROS-dependent and is accompanied by upregulation of heme oxygenase-1.

Abstract

PURPOSE:

To delineate a role for reactive oxygen species (ROS) induction in adaphostin-induced apoptosis in glioblastoma cells.

METHODS:

Three glioblastoma cell lines with different sensitivities to adaphostin were characterized for sensitivity to an oxidant, tert-butyl hydroperoxide. The degree and duration of the ROS levels was assessed in the three cell lines after adaphostin exposure. Antioxidant protein levels were evaluated by Western blotting.

RESULTS:

Of the three glioblastoma cell lines, the U87 cells were least sensitive to adaphostin. These cells were also least sensitive to tert-butyl hydroperoxide, indicating that sensitivity to a direct oxidant stress mirrors the cells' adaphostin sensitivities. In addition, the antioxidant N-acetylcysteine, (NAC) was protective against adaphostin-induced apoptosis. Direct measurement of intracellular peroxides showed a transient increase in the two less sensitive cell lines (U87 and LN18) which diminishes by 24 h. In contrast, U251 cells, which are most sensitive to adaphostin, display a sustained increase in the ROS levels. After the initial increase in intracellular peroxides, the heat shock protein and antioxidant heme oxygenase-1 (HO-1) was upregulated. Levels of other antioxidant proteins, such as catalase and thioredoxin, however, were not altered by adaphostin in glioblastoma cell lines. NAC attenuated HO-1 upregulation, confirming the time course analysis.

CONCLUSIONS:

These results suggest a primary role for ROS in adaphostin-induced apoptosis in glioblastoma. Our data indicate that the duration of intracellular ROS levels is a key factor in mediating sensitivity to adaphostin. Furthermore, upregulation of HO-1 is a novel molecular marker of adaphostin's action. The kinetics with which adaphostin upregulates HO-1 correlates with sensitivity to the drug. Taken together, our data indicate that a cell's ability to cope with ROS dictates sensitivity to adaphostin and conceivably other chemotherapies that cause redox perturbations.

• Authors: Jason Long, Tejas Manchandia, Kechen Ban, Shan Gao, Claudia Miller, Joya Chandra
• Journal: Cancer chemotherapy and pharmacology (Cancer Chemother Pharmacol) Vol. 59 Issue 4 Pg. 527-35 (Mar 2007) ISSN: 0344-5704 [Print] Germany
• PMID: 16924499 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Hydroquinones
• NSC 680410
• RNA, Messenger
• Reactive Oxygen Species
• Heme Oxygenase-1
• Fusion Proteins, bcr-abl
• Glutathione
• Adamantane

Topics

• Adamantane (analogs & derivatives, pharmacology)
• Antineoplastic Agents (pharmacology)
• Apoptosis (drug effects)
• Cell Line, Tumor
• DNA Fragmentation (drug effects)
• Fusion Proteins, bcr-abl (antagonists & inhibitors)
• Glioblastoma (drug therapy, metabolism)
• Glutathione (analysis)
• Heme Oxygenase-1 (genetics)
• Humans
• Hydroquinones (pharmacology)
• RNA, Messenger (analysis)
• Reactive Oxygen Species (metabolism)
• Up-Regulation