Oxidative Stress and Drug Resistance in Cancer

Abstract

Increased generation of reactive oxygen species (ROS) is observed in many types of cancer cells. Besides the well-recognized effect of ROS in causing mutations and promoting cancer cell growth, recent evidence further suggests the involvement of oxidative stress in anticancer drug resistance. Consistent with the tumor-promoting effect of ROS, many in vitro studies have reported tumor-suppressing properties of ROS-scavenging enzymes. However, enhancement of those enzymes in tumor cells in vivo has been implicated in chemoresistance and seems to be associated with poor prognosis. In this chapter, we summarized the relevant observations in the field and discuss evidences that may explain these seemingly paradoxical findings. Malignant transformation is often associated with a moderate increase in cellular ROS content as a result of evelvated ROS production and/or decreased ROS-scavenging capacity. Because the increase in ROS stress may induce oxidative damage of cellular components leading to cell death, cancer cells that are able to survive the intrinsic stress and develop tumor must be equipped with sufficient adaptive mechanisms to tolerate the ROS stress. The adaptation processes involve activation of certain redox-sensitive transcription factors, which consequently lead to increased expression of the downstream genes encoding various ROS-scavenging enzymes, and redox-sensitive survival machineries. These adaptation mechanisms lead to increase in cell survival capacity in response to stress and alteration in drug metabolism and transport, which together confer drug resistance. Therefore, strategies to modulate cellular adaptation to oxidative stress may be used as an effective approach to overcome drug resistance in cancer cells under intrinsic stress.