Susceptibility to Oxidative Stress - A Leukemic Cell’s Achilles’ Heel?

If validated, these findings could have particularly important implications for the treatment of hematologic malignancies. It has long been known that tumor cells may display higher levels of ROS than their normal counterparts. Interpretation of the significance of this phenomenon has been complicated by evidence that ROS play diverse and, on occasion, opposing roles in cellular survival and behavior. For example, at high concentrations, ROS damage DNA and lipid membranes and induce mitochondrial dysfunction culminating in apoptosis. However, at lower concentrations, ROS can act as signaling molecules and may contribute to cell proliferation among other functions. In the case of Bcr/Abl+ hematopoietic malignancies (e.g., CML), ROS induced by the Bcr/Abl oncoprotein have been implicated in the induction of mutations responsible for disease progression or drug resistance. Thus, the net effect of ROS generation may depend upon multiple factors, including cell context, the degree of oxidative injury, and perhaps the nature of the inciting stimulus.

The possibility that transformed cells display greater susceptibility to oxidative damage takes on added significance in view of emerging insights into the mechanism of action of several novel “targeted agents” and provides a possible theoretical basis for their therapeutic selectivity. In this context, histone deacetylase inhibitors (HDACIs), which are currently undergoing extensive evaluation in the treatment of hematologic malignancies, are known to kill leukemic cells through the selective induction of oxidative injury. In addition, proteasome inhibitors like Bortezomib, which in preclinical studies preferentially kill transformed cells, can also exert their lethal effects through induction of ROS. Other studies involving agents like 2-medroxyestradiol, arsenic trioxide, or the tyrphostin adaphostin, administered alone or in combination with other targeted agents, point to oxidative injury as a basis for therapeutic selectivity.

The possibility that the Bcr/Abl kinase or dysregulated RAS, which is frequently mutated in hematopoietic malignancies, might predispose cells to oxidative injury-induced cell death has very obvious clinical implications, particularly in diseases like leukemia. It raises the possibility that a) certain agents might preferentially induce ROS in leukemic cells¹ , and b) leukemic cells may be intrinsically less capable of surviving these insults. It also suggests that strategies combining novel agents, each of which may preferentially induce ROS in transformed cells² , might be a particularly appropriate strategy in this setting. In view of ongoing efforts to develop such clinical strategies, answers to these questions should begin to emerge in the near future.