Free radical stress in chronic lymphocytic leukemia cells and its role in cellular sensitivity to ROS-generating anticancer agents.
2-Methoxyestradiol (2-ME), a new anticancer 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 (O(2)-) by inhibition of SOD depends on the cellular generation of O(2)-, 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 O(2)- contents and the cytotoxic activity of 2-ME in primary leukemia cells from 50 patients with chronic lymphocytic leukemia (CLL). Quantitation of O(2)- revealed that the basal cellular O(2)- contents are heterogeneous among patients with CLL. The O(2)- levels were significantly higher in CLL cells from patients with prior chemotherapy. CLL cells with higher basal O(2)- contents were more sensitive to 2-ME in vitro than those with lower O(2)- contents. There was a significant correlation between the 2-ME-induced O(2)- 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 O(2)- 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.
Zhou
Yan
Y
Department of Molecular Pathology, The University of Texas M. D. Anderson Cancer Center, Houston, TX 77030, USA.
Hileman
Elizabeth O
EO
Plunkett
William
W
Keating
Michael J
MJ
Huang
Peng
P
D000077584:2-Methoxyestradiol; D000970:Antineoplastic Agents / Q000633:toxicity*; D002470:Cell Survival / Q000187:drug effects; D004958:Estradiol / Q000031:analogs & derivatives / Q000633:toxicity*; D016166:Free Radical Scavengers / Q000494:pharmacology*; D005609:Free Radicals / Q000378:metabolism; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000473:pathology*; D017382:Reactive Oxygen Species / Q000378:metabolism / Q000494:pharmacology*; D013481:Superoxides / Q000378:metabolism; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D016166:Free Radical Scavengers; D005609:Free Radicals; D017382:Reactive Oxygen Species; D013481:Superoxides; D004958:Estradiol; D000077584:2-Methoxyestradiol