Reactive oxygen species (ROS): Modulator of response to cancer therapy in non-small-cell lung carcinoma (NSCLC)

Abstract

Oxidative stress, caused by an imbalance between oxidants and antioxidants, is implicated in the etiology and progression of many types of cancer including lung cancer. The most common type of lung cancer, NSCLC, is the leading cause of cancer-related deaths worldwide. The lung tissue is particularly vulnerable to oxidative stress because of its direct interface with ambient air which exposes it to a variety of oxidants. In order to protect itself from oxidative stress, lung tissue is equipped with a robust endogenous antioxidant defense system mostly controlled by the redox-sensitive transcription factor Nrf2 which is negatively regulated by Keap1 protein. Lung cancer cells are reported to contain increased levels of ROS. However, administration of antioxidants has failed to show any obvious effectiveness in the prevention or cure of lung cancer. On the other hand, a prooxidant approach has been proposed to successfully kill cancer cells by generating ROS. Cancer cells, owing to their high basal ROS, are considered to be more vulnerable to the toxic effect of exogenous ROS-generating agents as opposed to normal cells. A major challenge in this mode of therapy is the acquisition of drug resistance in cancer cells. This is attributed to an elevation in the antioxidant system in cancer cells, leading to "redox adaptation, "which facilitates survival under enhanced oxidative stress. Incidentally, lung cancer cells have been reported to exhibit constitutive overexpression of Nrf2. Therefore, impairment of the Nrf2/Keap1 antioxidant pathway might be a promising strategy to control NSCLC. In this chapter, the importance of ROS as a signaling molecule in regulating some of the hallmark feature of cancer, such as proliferation, apoptosis, angiogenesis, metastasis, etc., is discussed. Furthermore, the various ROS-modulating therapeutic approaches to treat NSCLC presently under investigation at experimental and clinical setting are also discussed.