Submitted August 16, 2002
Accepted January 4, 2003
Free radical stress in chronic lymphocytic leukemia cells and its role in cellular sensitivity to ROS-generating anticancer agents
Yan Zhou, Elizabeth O Hileman, William Plunkett, Michael J Keating, and Peng Huang*
Department of Molecular Pathology, The University of Texas M. D. Anderson Cancer Center, Houston, TX, USA
Department of Experimental Therapeutics, The University of Texas M. D. Anderson Cancer Center, Houston, TX, USA
Department of Leukemia, The University of Texas M. D. Anderson Cancer Center, Houston, TX, USA
* Corresponding author; email: phuang{at}mdanderson.org.
2-Methoxyestradiol (2-ME), a new anticancer agent currently in clinical trials, has been demonstrated to inhibit superoxide dismutase (SOD) and induce apoptosis in leukemia cells through a free-radical-mediated mechanism. Because the accumulation of superoxide (O2-) by inhibition of SOD depends upon the cellular generation of O2-, we hypothesized that the endogenous production of superoxide may be a critical factor that affects the anti-leukemia 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 CLL patients. 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 anti-leukemia activity and to overcome drug resistance. Such a combination strategy may have potential clinical applications.
