Review
Role of reactive oxygen species in apoptosis: implications for cancer therapy

https://doi.org/10.1016/S1357-2725(99)00088-6Get rights and content

Abstract

Reactive oxygen species are widely generated in biological systems. Consequently humans have evolved antioxidant defence systems that limit their production. Intracellular production of active oxygen species such as –radical dotOH, O2 and H2O2 is associated with the arrest of cell proliferation. Similarly, generation of oxidative stress in response to various external stimuli has been implicated in the activation of transcription factors and to the triggering of apoptosis. Here we review how free radicals induce DNA sequence changes in the form of mutations, deletions, gene amplification and rearrangements. These alterations may result in the initiation of apoptosis signalling leading to cell death, or to the activation of several proto-oncogenes and/or the inactivation of some tumour suppressor genes. The regulation of gene expression by means of oxidants, antioxidants and the redox state remains as a promising therapeutic approach. Several anticarcinogenic agents have been shown to inhibit reactive oxygen species production and oxidative DNA damage, inhibiting tumour promotion. In addition, recombinant vectors expressing radical-scavenging enzymes reduce apoptosis. In conclusion, oxidative stress has been implicated in both apoptosis and the pathogenesis of cancer providing contrived support for two notions: free radical reactions may be increased in malignant cells and oxidant scavenging systems may be useful in cancer therapy.

Introduction

As a consequence of aerobic metabolism small amounts of reactive oxygen species (ROS), including hydroxyl radicals (radical dotOH), superoxide anions (O2radical dot), singlet oxygen (1O2) and hydrogen peroxide (H2O2), are constantly generated in organisms [1]. Cellular antioxidants act in concert to detoxify these species but, when the balance is disrupted, a condition referred to as oxidative stress exists. If oxidative stress persists, oxidative damage to critical biomolecules (including oxidant-induced damage to the genome) accumulates and eventually results in several biological effects ranging from alterations in signal transduction and gene expression to mitogenesis, transformation, mutagenesis and cell death [2], [3].

Apoptosis and cancer are opposed phenomena, but ROS have been widely reported to play a key role in both. Evidences that apoptosis can be induced by ROS is provided by studies in which mediators of apoptosis, induce intracellular production of ROS or are inhibited by the addition of antioxidants. Although the mechanism involved is still controversial redox status and/or hydrogen peroxide have both been proposed as critical factors [4], [5]. In addition, induction of carcinogenesis has been clearly linked to oxidative DNA damage [3] and the DNA oxidative product, 8-oxo-2′-deoxyguanosine, has been reported to be highly mutagenic [6]. ROS are thought to contribute to carcinogenesis through interference with signal cascade systems, including among others, the nuclear transcription factor kappa B (NFκB), activated protein-1 (AP-1), phospholipase A2, mitogen-activated protein kinases (MAPKs) and c-Jun kinase [7], [8], [9], [10].

Cells react rapidly to redox imbalance with a plethora of biological responses, including cell cycle-specific growth arrest, gene transcription, initiation of signal transduction pathways and repair of damaged DNA. These early events are likely to determine whether a cell will necrose, senesce, apoptose or survive and proliferate [11].

Many tumours have been associated with inhibition of apoptosis, follicular lymphomas, carcinomas with p53 mutations: medullary breast carcinoma, lung cancer, colorectal cancer; and hormone-dependent tumours: such as breast, prostate and ovarian cancer [12], [13], [14].

Section snippets

Source and control of ROS production

In aerobic cells, the most important sources of O2radical dot are the electron transport chains of mitochondria and endoplasmic reticulum. In mitochondria, ROS formation is significantly increased by uncouplers of oxidative phosphorylation, hyperbaric O2 treatment, pathologic conditions such as ischemia/reperfusion syndrome, ageing, etc and alterations of mitochondrial lipids occurring during deficiency of polyunsaturated fatty acids and lipoperoxidation processes. In the endoplasmic reticulum (RE)

Mechanisms for ROS detoxification

To avoid redox imbalance and oxidative DNA damage, a wide array of enzymatic and nonenzymatic antioxidant defences exist. Primary defence mechanisms prevent oxidative damage by scavenging reactive species directly. The primary defence system includes superoxide dismutase (SOD), glutathione peroxidase (GPX), catalase (CAT) and thioredoxin reductase. Secondary defence's combat processes elicited by free radicals. Main compounds belonging to the secondary defence system are ascorbic acid (vitamin

ROS and activation of apoptosis

In the apoptotic process initial stress-induced damage does not kill cells directly, rather it triggers an apoptotic signalling programme that leads to cell death [28].

Apoptotic cell death is characterized by controlled autodigestion of the cell. This differs from necrosis by distinct morphological and biochemical features, such as chromatin condensation, membrane surface blebbing, oligonucleosomal DNA fragmentation and finally, the breakdown of the cell into a series of smaller units

Apoptosis, oxidative injury and pathogenesis

O2 therapy, a widely used component in life-saving intensive care, can cause lung injury, although hyperoxia kills cells via necrosis, not apoptosis [46]. Nevertheless cellular oxidant injury can occur without apoptosis and certain apoptotic mechanisms (i.e. fas-mediated) do not have requirements for ROS [47], [48], apoptosis, oxidant injury and ROS are strongly related.

Formation of ROS following irradiation is thought to be a major determinant of cellular damage. Recombinant adenoviral vectors

Antioxidants against tumours

Antioxidant enzymes can antagonize initiation and promotion phases of carcinogenesis and they are reduced in many malignancies. The most commonly decreased enzyme is the mitochondrial Mn-SOD. This has led to suggestions that Mn-SOD might be a new type of tumour-suppressor gene. However, observations tend to ascribe the deficiency of the Mn-SOD activity to a defect in the expression of the gene rather than to its deletion. Transition metals (Mn, Fe) have been found to be highly deficient in some

Directions for future research

Critical steps in the signal transduction cascade are sensitive to oxidants and antioxidants. At least two well-defined transcription factors (NFκB and AP-1) have been identified to be regulated by the intracellular redox state. Binding sites of these redox-regulated transcription factors are located in the promoter region of a large variety of genes that are directly involved in the pathogenesis of cancer and other diseases. Biochemical and clinical studies indicate that antioxidant therapy

Acknowledgements

We wish to thank I. Núñez de Castro and M.A. Medina for critically reading the manuscript, N. McVeigh and C. Segura for the revision of the spelling and the grammar and post-graduate students C. Pérez-Gómez, R. Rosado and J.M. Segura for their help in the bibliographic search. This work was supported by project SAF98-0150 (Ministry of Education, Spain). To the memory of Emilio Matés Sánchez.

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