ROS stress in cancer cells and therapeutic implications

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Abstract

Reactive oxygen species (ROS) are constantly generated and eliminated in the biological system, and play important roles in a variety of normal biochemical functions and abnormal pathological processes. Growing evidence suggests that cancer cells exhibit increased intrinsic ROS stress, due in part to oncogenic stimulation, increased metabolic activity, and mitochondrial malfunction. Since the mitochondrial respiratory chain (electron transport complexes) is a major source of ROS generation in the cells, the vulnerability of the mitochondrial DNA to ROS-mediated damage appears to be a mechanism to amplify ROS stress in cancer cells. The escalated ROS generation in cancer cells serves as an endogenous source of DNA-damaging agents that promote genetic instability and development of drug resistance. Malfunction of mitochondria also alters cellular apoptotic response to anticancer agents. Despite the negative impacts of increased ROS in cancer cells, it is possible to exploit this biochemical feature and develop novel therapeutic strategies to preferentially kill cancer cells through ROS-mediated mechanisms. This article reviews ROS stress in cancer cells, its underlying mechanisms and relationship with mitochondrial malfunction and alteration in drug sensitivity, and suggests new therapeutic strategies that take advantage of increased ROS in cancer cells to enhance therapeutic activity and selectivity.

Introduction

Therapeutic selectivity and drug resistance are two major issues in cancer chemotherapy. Strategies to improve therapeutic selectivity largely rely on our understanding of the biological difference between cancer and normal cells, and on the availability of therapeutic agents that target biological events critical for cancer cells but not essential for normal cells. Evidence from recent studies suggests that cancer cells, compared to normal cells, are under increased oxidative stress associated with oncogenic transformation, alterations in metabolic activity, and increased generation of reactive oxygen species (ROS) (Toyokuni et al., 1995, Hileman et al., 2001, Hileman et al., 2003, Kang and Hamasaki, 2003, Behrend et al., 2003). The increased amounts of ROS in cancer cells may have significant consequences, such as stimulation of cellular proliferation, promotion of mutations and genetic instability, and alterations in cellular sensitivity to anticancer agents. It is logical to speculate that the biochemical and molecular changes caused by ROS may contribute to the development of a heterogeneous cancer cell population and the emergence of drug-resistant cells during disease progression. While the mechanisms responsible for drug resistance are extremely complex and may depend on the mechanism of action of anticancer agents and the genetic background of the cancer cells (Fojo, 2002, Morin, 2003, Vasilevskaya and O’Dwyer, 2003), ROS-mediated DNA lesions and mutations are likely to provide a mechanism through which drug-resistant variants constantly evolve. However, because ROS are chemically active and can inflict severe cellular damage, the very fact that cancer cells are under increased intrinsic ROS stress may also provide a unique opportunity to kill the malignant cells based on their vulnerability to further ROS insults. As such, this biochemical characteristic is likely to have significant therapeutic implications.

ROS are broadly defined as oxygen-containing chemical species with reactive chemical properties, and include free radicals such as superoxide (O2radical dot) and hydroxyl radicals (HOradical dot), which contain an unpaired electron, and non-radical molecules such hydrogen peroxide (H2O2). In biological systems, ROS are constantly generated through a variety of pathways, including both enzyme-catalyzed reactions and non-enzyme reactions. During oxidative phosphorylation in mitochondria, electrons are delivered through the respiratory chain, and a proton gradient is established across the inner mitochondrial membrane as energy source for ATP synthesis. One important biochemical event associated with this metabolic process is the production of superoxide. Some electrons may escape from the mitochondrial electron transport chain, especially from complexes I and III, and react with molecular oxygen to form superoxide (Saybasili et al., 2001, Staniek et al., 2002). It is estimated that about 2% of the oxygen consumed by the mitochondria is reduced by the bifurcated electrons to form superoxide, which is subsequently converted to hydrogen peroxide (Boveris and Chance, 1973, Fridovich, 1995). Because superoxide radicals are constantly generated during respiration and can be converted to H2O2 and other reactive oxygen species, mitochondria are considered the major source of cellular ROS (Richter et al., 1995, Halliwell and Gutteridge, 1999), and are likely to play a significant role in ROS stress in cancer cells. In addition, ROS can also be produced by a family of membrane-bound enzymes such as NAD(P)H oxidases, which seem to affect cell proliferation and apoptosis (Wientjes and Segal, 1995, Vignais, 2002, Brar et al., 2003). The increase of ROS stress in cancer cells and its biological consequences and therapeutic implications will be reviewed in this article.

Section snippets

Intrinsic ROS stress in cancer cells

The biological functions of ROS and its potential roles in cancer development and disease progression have been investigated for several decades. Cancer cells are known to be metabolically active and under increased oxidative stress, presumably associated with uncontrolled cell proliferation and dysfunction of metabolic regulation. Table 1 summarizes some key findings relevant to ROS stress in cancer, the potential underlying mechanisms, and biological consequences.

Increased ROS in cancer cells

Mechanisms of increased ROS stress in cancer cells

Despite the prevalent ROS stress observed in a wide spectrum of human cancers, the precise mechanisms responsible for such stress remain to be defined. The degree of oxidative stress in a cell is dependent on the dynamic balance between the ROS generation and elimination processes. Under physiological conditions, the maintenance of an appropriate level of intracellular ROS is important in keeping the redox balance and signaling cellular proliferation (Murrell et al., 1990, Nicotera et al., 1994

Consequences of increased ROS in cancer cells

Increase in ROS stress can induce various biological responses, ranging from a transient growth arrest and adaptation, increase in cellular proliferation, permanent growth arrest or senescence, apoptosis, and necrosis (Davies, 1999). The actual outcomes are likely to be dependent on the cellular genetic background, the types of the specific ROS involved, and the levels and duration of the ROS stress.

Rationale

The intrinsic oxidative stress of cancer cells is a feature that can be exploited therapeutically. Kong and Lillehei speculated that many chemotherapeutic agents and ionizing radiation exert their killing effect on cancer cells by the production of free radicals leading to irreversible cell injury, and that overproduction of ROS in cancer cells may exhaust the capacity of SOD and other adaptive antioxidant defenses. They further proposed a therapeutic strategy using antioxidant inhibitors

Summary and future perspective

Compelling evidence suggests that cancer cells are inherently under increased ROS stress due to a variety of complex factors. As illustrated in Fig. 1, oncogenic signals, active energy metabolism associated with uncontrolled cell proliferation, and malfunction of the mitochondrial respiration associated with mtDNA mutations are possible mechanisms contributing to increased ROS generation in the malignant cells. On one hand, the increase of ROS generation in cancer cells may further stimulate

Acknowledgements

The studies in the authors’ laboratory were supported in part by grants CA77339, CA85563, CA100428, CA81534, and CA55164 from the National Cancer Institute, the National Institutes of Health.

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