Oxidative stress and lipid peroxidation products in cancer progression and therapy

Abstract

The generation of reactive oxygen species (ROS) and an altered redox status are common biochemical aspects in cancer cells. ROS can react with the polyunsaturated fatty acids of lipid membranes and induce lipid peroxidation. The end products of lipid peroxidation, 4-hydroxynonenal (HNE), have been considered to be a second messenger of oxidative stress. Beyond ROS involvement in carcinogenesis, increased ROS level can inhibit tumor cell growth. Indeed, in tumors in advanced stages, a further increase of oxidative stress, such as that occurs when using several anticancer drugs and radiation therapy, can overcome the antioxidant defenses of cancer cells and drive them to apoptosis. High concentrations of HNE can also induce apoptosis in cancer cells. However, some cells escape the apoptosis induced by chemical or radiation therapy through the adaptation to intrinsic oxidative stress which confers drug resistance. This paper is focused on recent advances in the studies of the relation between oxidative stress, lipid peroxidation products, and cancer progression with particular attention to the pro-oxidant anticancer agents and the drug-resistant mechanisms, which could be modulated to obtain a better response to cancer therapy.

Figure 1

Number of published papers/year, concerning the oxidative stress in cancer therapy.

Figure 2

ROS level in normal, cancer, and chemo- and radio-resistant cancer cells. Under physiological conditions, normal cells maintain redox homeostasis with a low level of basal ROS by controlling the balance between ROS generation (pro-oxidants) and elimination (antioxidant capacity). Normal cells can tolerate a certain level of exogenous ROS stress owing to their “reserve antioxidant capacity.” The antioxidant reserve can prevent cell transformation and cell death. In cancer cells, the increase in ROS generation from metabolic abnormalities and oncogenic signalling may trigger a redox adaptation response, leading to an upregulation of antioxidant capacity, high ROS generation, and elimination to maintain the ROS levels below the toxic threshold. A further increase of ROS stress and in lipid peroxidation products in cancer cells (black space) using exogenous ROS-modulating agents or lipid peroxidation substrates is likely to cause elevation of ROS above the threshold level, leading to cell death. This might constitute a biochemical basis to design therapeutic strategies to selectively kill cancer cells using ROS-mediated mechanisms. Finally, excessive increase in intracellular ROS levels (and in lipid peroxidation products) as mediated by radiation therapy and chemotherapeutics may be repulsed by the tumour cells through an increase in the expression of endogenous antioxidants. This redox adaptation not only enables the cancer cells to survive under increased ROS stress, but also provides a mechanism of resistance to many anticancer agents and radiation therapy.