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Adaphostin Cytoxicity in Glioblastoma Cells Is ROS-dependent and Is Accompanied by Upregulation of Heme oxygenase-1

Adaphostin Cytoxicity in Glioblastoma Cells Is ROS-dependent and Is Accompanied by Upregulation of Heme oxygenase-1

Jason Long, Tejas Manchandia, Kechen Ban, Shan Gao, Claudia Miller, Joya Chandra

Cancer Chemother Pharmacol. 2007 Mar;59(4):527-35.

PMID: 16924499

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.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP241127582	Adaphostin		241127-58-2	Price

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