TY - JOUR
T1 - Free radical stress in chronic lymphocytic leukemia cells and its role in cellular sensitivity to ROS-generating anticancer agents
AU - Zhou, Yan
AU - Hileman, Elizabeth O.
AU - Plunkett, William
AU - Keating, Michael J.
AU - Huang, Peng
PY - 2003/5/15
Y1 - 2003/5/15
N2 - 2-Methoxyestradiol (2-ME), a new anti-cancer agent currently in clinical trials, has been demonstrated to inhibit superoxide dismutase (SOD) and to induce apoptosis in leukemia cells through a free radical-mediated mechanism. Because the accumulation of superoxide (O2-) by inhibition of SOD depends on the cellular generation of O2-, we hypothesized that the endogenous production of superoxide may be a critical factor that affects the antileukemia activity of 2-ME. In the present study, we investigated the relationship between cellular O2- contents and the cytotoxic activity of 2-ME in primary leukemia cells from 50 patients with chronic lymphocytic leukemia (CLL). Quantitation of O2- revealed that the basal cellular O2- contents are heterogeneous among patients with CLL. The O2- levels were significantly higher in CLL cells from patients with prior chemotherapy. CLL cells with higher basal O2- contents were more sensitive to 2-ME in vitro than those with lower O2- contents. There was a significant correlation between the 2-ME-induced O2- increase and the loss of cell viability. Importantly, addition of arsenic trioxide, a compound capable of causing reactive oxygen species (ROS) generation, significantly enhanced the activity of 2-ME, even in the CLL cells that were resistant to 2-ME alone. These results suggest that the cellular generation of O2- plays an important role in the cytotoxic action of 2-ME and that it is possible to use exogenous ROS-producing agents such as arsenic trioxide in combination with 2-ME to enhance the antileukemia activity and to overcome drug resistance. Such a combination strategy may have potential clinical applications.
AB - 2-Methoxyestradiol (2-ME), a new anti-cancer agent currently in clinical trials, has been demonstrated to inhibit superoxide dismutase (SOD) and to induce apoptosis in leukemia cells through a free radical-mediated mechanism. Because the accumulation of superoxide (O2-) by inhibition of SOD depends on the cellular generation of O2-, we hypothesized that the endogenous production of superoxide may be a critical factor that affects the antileukemia activity of 2-ME. In the present study, we investigated the relationship between cellular O2- contents and the cytotoxic activity of 2-ME in primary leukemia cells from 50 patients with chronic lymphocytic leukemia (CLL). Quantitation of O2- revealed that the basal cellular O2- contents are heterogeneous among patients with CLL. The O2- levels were significantly higher in CLL cells from patients with prior chemotherapy. CLL cells with higher basal O2- contents were more sensitive to 2-ME in vitro than those with lower O2- contents. There was a significant correlation between the 2-ME-induced O2- increase and the loss of cell viability. Importantly, addition of arsenic trioxide, a compound capable of causing reactive oxygen species (ROS) generation, significantly enhanced the activity of 2-ME, even in the CLL cells that were resistant to 2-ME alone. These results suggest that the cellular generation of O2- plays an important role in the cytotoxic action of 2-ME and that it is possible to use exogenous ROS-producing agents such as arsenic trioxide in combination with 2-ME to enhance the antileukemia activity and to overcome drug resistance. Such a combination strategy may have potential clinical applications.
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U2 - 10.1182/blood-2002-08-2512
DO - 10.1182/blood-2002-08-2512
M3 - Article
C2 - 12531810
AN - SCOPUS:0037926836
SN - 0006-4971
VL - 101
SP - 4098
EP - 4104
JO - Blood
JF - Blood
IS - 10
ER -