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Blood, 1 August 2001, Vol. 98, No. 3, pp. 805-813
NEOPLASIA
Ascorbic acid enhances arsenic trioxide-induced cytotoxicity
in multiple myeloma cells
Jennifer M. Grad,
Nizar J. Bahlis,
Isildinha Reis,
Marc M. Oshiro,
William S. Dalton, and
Lawrence H. Boise
From the Department of Microbiology and Immunology,
Division of Hematology and Oncology, Sylvester Cancer Center,
University of Miami School of Medicine, Florida; and the H. Lee Moffitt
Cancer Center and Research Institute, University of South Florida
College of Medicine, Tampa, FL.
Multiple myeloma (MM) is a clonal B-cell malignancy characterized
by slow-growing plasma cells in the bone marrow (BM). Patients with MM
typically respond to initial chemotherapies; however, essentially all
progress to a chemoresistant state. Factors that contribute to the
chemorefractory phenotype include modulation of free radical
scavenging, increased expression of drug efflux pumps, and changes in
gene expression that allow escape from apoptotic signaling. Recent data
indicate that arsenic trioxide (As2O3) induces
remission of refractory acute promyelocytic leukemia and apoptosis of
cell lines overexpressing Bcl-2 family members; therefore, it was
hypothesized that chemorefractory MM cells would be sensitive to
As2O3. As2O3 induced
apoptosis in 4 human MM cell lines: 8226/S, 8226/Dox40, U266, and
U266/Bcl-xL. The addition of interleukin-6 had no effect on
cell death. Glutathione (GSH) has been implicated as an inhibitor of
As2O3-induced cell death either through
conjugating As2O3 or by sequestering reactive
oxygen induced by As2O3. Consistent with this
possibility, increasing GSH levels with N-acetylcysteine attenuated
As2O3 cytotoxicity. Decreases in GSH have been
associated with ascorbic acid (AA) metabolism. Clinically relevant
doses of AA decreased GSH levels and potentiated
As2O3-mediated cell death of all 4 MM cell
lines. Similar results were obtained in freshly isolated human MM
cells. In contrast, normal BM cells displayed little sensitivity to
As2O3 alone or in combination with AA.
Together, these data suggest that As2O3 and AA
may be effective antineoplastic agents in refractory MM and that AA
might be a useful adjuvant in GSH-sensitive therapies.
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