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Oxidative stress and apoptosis: Impact on cancer therapy

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ABSTRACT

It is well established that some chemotherapeutic agents and radiation therapy generate reactive oxygen species (ROS) in patients during cancer therapy. Free radicals, particularly ROS have been proposed as common mediators for apoptosis. Recent studies have demonstrated that the mode of cell death depends on the severity of the oxidative damage. This review will address some of the current paradigms of oxidative stress, and antioxidants on apoptosis, and discuss the potential mechanisms by which oxidants can regulate apoptotic pathways. It will also review new developments in eliminating cancer cells by selectively inducing apoptosis. © 2007 Wiley‐Liss, Inc. and the American Pharmacists Association J Pharm Sci 96: 2181–2196, 2007

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INTRODUCTION

Oxidative stress is a biochemical condition that is characterized by the imbalance between the presence of relatively high levels of toxic reactive species, principally consisting of reactive oxygen species (ROS), reactive nitrogen species (RNS), and the antioxidative defense mechanisms.1., 2., 3. ROS and RNS are organic or inorganic molecules that have an odd number of electrons. These molecules are formed in vivo via oxidation‐reduction reactions and are highly reactive. While oxygen is an

INTRINSIC OXIDATIVE STRESS IN CANCER CELLS

The biological functions of oxidative stress and its potential role in cancer development and progression have been investigated for several decades. Cancer itself induces oxidative stress, actually ROS levels have been found to be significantly higher and GPX and SOD activities significantly lower in cancer patients than controls; on the same line serum levels of IL‐1 beta, IL‐6, TNF‐α, C‐reactive protein, and fibrinogen are significantly higher and serum levels of IL‐2 and leptin

OXIDATIVE STRESS INDUCED BY CANCER THERAPY

It is well established that some chemotherapeutic agents and radiation therapy generate ROS in patients during cancer therapy.5, 21

Chemotherapy agents can be divided into several categories: alkylating agents (e.g., cyclophosphamide, ifosfamide), anthracycline antibiotics which affect nucleic acids (e.g., doxorubicin, bleomycin), platinum compounds (e.g., cisplatin), mitotic inhibitors (e.g., vincristine), antimetabolites (e.g., 5‐fluorouracil), camptothecin derivatives (e.g., topotecan),

CELLULAR RESPONSES TO OXIDATIVE STRESS IN CANCER CELLS

Increased cellular oxidative stress changes the equilibrium in cell redox status and triggers several reactions.25 Oxidative stress can induce various biological responses, including a transient growth arrest and adaptation, gene transcription, initiation of signal transduction pathways, and repair of damaged DNA.26, 27 These events determine whether a cell will undergo necrosis, senescence, apoptosis, or will survive and proliferate.27 The extent of these responses will depend on the cellular

ADAPTATION

Several cellular adaptive defense mechanisms including antioxidant enzymes and redox buffering systems help cells to regulate mild oxidative stress. However, such adaptation processes have limited capacity in cancer cells, and excess ROS production during cancer therapy may bring oxidative stress to a level that triggers cell death.14

ENHANCED CELL PROLIFERATION

ROS may serve also as messengers in cellular signaling transduction pathways, promote cellular growth and proliferation, and contribute to cancer development.14, 19 Direct ROS interaction with specific receptors and modulation of the redox states of signaling molecules are the mechanisms responsible for stimulation of cell proliferation. A change in the redox status of a signaling molecule may lead to stimulation of cell growth and cell proliferation. Oxidative modifications of redox‐sensitive

DNA DAMAGE

DNA damage caused by ROS leads to the generation of oxidized bases (e.g., 8‐oxo‐dG), DNA strand breaks, DNA intra‐strand adducts, and DNA–protein crosslinks.14, 31, 32 Oxidative modifications of DNA bases may result in mutations during DNA replication due to base pair mismatching.14, 33 Mitochondrial DNA (mtDNA) is more vulnerable to damage by ROS than nuclear DNA (nDNA). mtDNA mutations are frequently detected in cancer cells due to its close proximity to the site of ROS generation, its lack

CELLULAR INJURY AND CELL DEATH

Excessive production of ROS may damage several cellular components including DNA, protein, and lipid membranes.14, 36 Oxidation of antioxidant enzymes reduces the ability of cells to eliminate oxidative stress. Direct oxidative modifications of amino acid side chains and ROS‐mediated peptide cleavage may cause protein damage.37 Lipid membranes are also vulnerable to ROS attack. Damage to the mitochondrial membrane may cause release of cytochrome c and activate the apoptotic pathway. Excess ROS

PATHWAYS OF CASPASE ACTIVATION

There are two major pathways for inducing apoptosis, one begins with ligation of cell surface death receptors (extrinsic pathway), and another involves mitochondrial release of cytochrome c (intrinsic pathway).46 In the extrinsic pathway, apoptosis is induced by death ligands of the cell surface death receptors.42 Death receptors detect the presence of extracellular death signals and activate death caspases, causing apoptosis of the cell within hours.50 Death receptors contain a homologous

APOPTOSIS INDUCED BY ROS DURING CANCER THERAPY

Numerous studies have demonstrated that a wide range of anticancer agents induce apoptosis in malignant cells in vitro.46, 70., 71., 72., 73. In the apoptotic process, initial stress‐induced damage does not kill cells directly, rather it triggers an apoptotic signaling program that leads to cell death.27 Cell viability depends on the type of stress exerted on them. Free radicals, particularly ROS, have been proposed as common mediators for apoptosis.2 An acute generation of ROS, or transient

CONFLICTING VIEWS OF ANTIOXIDANT USE IN CANCER THERAPY

Since ROS plays a role in drug‐induced apoptosis, one might suspect that antioxidants may inhibit ROS and prevent apoptosis of cancer cells. There is an intense argument on the concurrent use of antioxidants with the conventional cancer treatments. An increasing number of patients have turned to such complementary treatments with antioxidants. In contrast, many oncologists have turned against antioxidants and warned their patients not to use them during conventional cancer therapy.97, 98 This

INDUCTION OF APOPTOSIS IN CANCER: THERAPEUTIC IMPLICATIONS

Excessive apoptosis has been blamed for several pathologies, including neurodegenerative diseases, ischemia‐reperfusion injury, graft‐versus‐host disease, and autoimmune disorders. Strategy for therapeutic intervention in these diseases involving excessive apoptosis might be caspase inhibition.43 In contrast, in order to prevent malignant tissues to grow, therapeutic intervention involves induction of apoptosis through caspase activation.43 Two main problems of chemotherapy are toxicity to

Acknowledgements

Our studies were supported by the Research Fund of Akdeniz University.

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