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Blood, Vol. 93 No. 1 (January 1), 1999:
pp. 268-277
Malignant Cells Can Be Sensitized to Undergo Growth Inhibition and
Apoptosis by Arsenic Trioxide Through Modulation of the Glutathione
Redox System
Jie Dai,
Rona S. Weinberg,
Samuel Waxman, and
Yongkui Jing
From the Rochelle Belfer Chemotherapy Foundation Laboratory, the
Division of Neoplastic Diseases, the Division of Hematology, the
Department of Medicine, Mount Sinai Medical Center, New York, NY.
Arsenic trioxide (As2O3) induces clinical
remission in acute promyelocytic leukemia (APL) with minimal toxicity
and apoptosis in APL-derived NB4 cells at low (1 to 2 µmol/L)
concentration. We examined the basis for NB4 cell sensitivity to
As2O3 to identify experimental conditions that
would render other malignant cells responsive to low concentrations of
As2O3. The intracellular glutathione (GSH)
content had a decisive effect on As2O3-induced
apoptosis. Highly sensitive NB4 cells had the lowest GSH and the
sensitivity of other cell lines was inversely proportional to their GSH
content. The t(14;18) B-cell lymphoma cell line had low GSH levels and sensitivity to As2O3 at levels slightly higher
than in APL cells. Experimental upmodulation of GSH content decreased
the sensitivity to As2O3. Ascorbic acid and
buthionine sulfoxide (BSO) decreased GSH to a greater extent, and
rendered malignant cells more sensitive to
As2O3. As2O3-induced
apoptosis was not enhanced by ascorbic acid in normal cells, suggesting
that the combination of ascorbic acid and As2O3
may be selectively toxic to some malignant cells. Ascorbic acid
enhanced the antilymphoma effect of As2O3 in
vivo without additional toxicity. Thus, As2O3
alone or administered with ascorbic acid may provide a novel therapy
for lymphoma.
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