Paradoxical action of reactive oxygen species in creation and therapy of cancer

doi:10.1016/j.ejphar.2014.04.023

European Journal of Pharmacology

Volume 735, 15 July 2014, Pages 150-168

https://doi.org/10.1016/j.ejphar.2014.04.023 Get rights and content

Abstract

A great number of comprehensive literature believe that reactive oxygen species (ROS) and their products play a significant role in cell homeostasis maintenance, tissue protection against further insults by controlling cells proliferation through inducing apoptosis, and defending against cancer. ROS is believed to be like a potential double-edged sword in both cancer progression and prevention. Although at low and moderate levels ROS affect some of the most essential mechanisms of cell survival such as proliferation, angiogenesis and tumor invasion, at higher levels these agents can expose cells to detrimental consequences of oxidative stress including DNA damage and apoptosis that result in therapeutic effects on cancer. Understanding the new aspects on molecular mechanisms and signaling pathways modulating creation and therapy of cancers by ROS is critical in development of therapeutic strategies for patients suffering from cancer. This paper presents a general overview and rationale of paradoxical action of ROS in creation and therapy of cancer, tests to be used, and examples of how it may be applied.

Introduction

Cancer, medically termed as malignant neoplasm, includes a wide spectrum of over 100 types of different diseases that can afflict humans with various etiologies and epidemiological distributions. The eruption of this condition is initiated by uncontrollable reproduction of cells in a specific part of the body and also failure in the mechanisms of cell death. Malignant tumors, formed by rapid division of cancerous cells, can invade and destroy surrounding tissues and organs. Spreading of cancerous tumors to distant parts of the body through the lymphatic system or bloodstream is known as metastasis (Stratton et al., 2009). Cancer is a major public health problem in the United States and many other parts of the world, with regard to the fact that it is responsible for a mortality of 1 in 4 deaths in US; the disease is ranked as the second cause of death after cardiac health problems (Rebecca Siegel and Ahmedin, 2012).

Most risk factors associated with cancer interact with cells through the generation of oxidative stress. This is a condition in which reactive oxygen species (ROS) and/or free radicals, namely superoxide ( ${O_{2}}^{-}$ ), hydroperoxyl radical ( ${HO}_{2}^{-}$ ), and hydroxyl radical (OH⁻), are produced intra- or extra-cellularly, and induce toxic impacts on cells. Oxidative stress can play an important role in the pathogenesis or treatment of cancer diseases. A great number of comprehensive literature believe that ROS and their products are responsible for important signaling functions, and play a significant role in cell homeostasis maintenance, tissue protection against further insults by developing preconditioning, gene transcription regulation, controlling cell proliferation by inducing apoptosis, and defending against cancer (Becker, 2004, Martin and Barrett, 2002, Nakashima et al., 2003). Under physiologic conditions, cells control ROS levels by the use of scavenging systems that balance ROS generation and elimination. But under oxidative stress conditions, excessive ROS can damage cellular proteins, lipids, and DNA, leading to fatal damages to cell that may contribute to carcinogenesis (Fausto, 2006).

Section snippets

Reactive oxygen species

ROS, as byproducts of oxygen metabolism, are constantly produced in the human body and removed by antioxidant defense. High chemical reactivity is a prominent characteristic of these chemical agents; therefore, these factors are believed to be toxic in cellular life (Auten and Davis, 2009). Given the higher stability of paired electrons positioned in an orbital compared to single electrons, it is expected that radicals express a higher degree of reactivity than non-radicals (Halliwell, 1991).

Controversy of free radical hypothesis

Although ROS was first implicated as deleterious and destructive in events such as ischemia reperfusion (IR) injury, later findings revealed that these agents could also be implicated in the processes involved in maintenance of homeostasis (Becker, 2004, Feinendegen, 2002). They can play an important role in preventing diseases through supporting the immune system, intervening in cell signaling and mediating apoptosis. On the other hand, they can also be responsible for carcinogenesis and

ROS sources

Mitochondrion is perhaps the most important in vivo source of ROS (Fig. 1). The mitochondrial electron transport chain (ETC) has several redox centers, which may leak electrons to molecular oxygen, serving as the primary producer of ROS in most of the tissues (Ott et al., 2007). Mitochondrial ETC generates primary ROS at two complexes, I and III. ${HO}_{2}^{-}$ and ${O_{2}}^{-}$ radicals are produced from ROS in a number of cellular reactions and by different enzymes, e.g., lipo-oxygenase (LOX), nicotinamide

Lipid peroxidation

Lipid peroxidation is the oxidative process of lipid degradation by ROS that are either by products of cellular metabolic reactions or oxidative stress (Marnet, 2002, Young and McEneny, 2001). Uncontrolled reaction of ROS with the present membrane lipids, especially polyunsaturated fatty acid chains, will lead to a myriad generation of free radicals produced in chain reaction that renders deterioration of the membranes (Feeney and Berman, 1976). The process consists of three chief steps in

Oxidant stress and inflammation

Inflammation is classified into two major stages: acute and chronic. As the initial stage, acute inflammation is mostly due to the “respiratory burst” caused by mast cells and leukocytes as a response against an exogenous invasion (Reuter et al., 2010). However, in the chronic stage the increased release of mediators such as metabolites of arachidonic acid, cytokines, and chemokines by inflammatory cells recruit inflammatory cells to the site of damage which will ultimately result in a higher

Oxidative therapy against cancer

Although oxidative stress, considered as the imbalance of ROS production and its clearance by antioxidant defenders, is the primary cause of injury to cellular components and thus cell death, recent researches propose that selective induction of oxidative stress might be utilized as an advantageous factor in certain conditions (Dawson and Kouzarides, 2012). As tumor cells are distinguished by abnormal oxidation state and extensive amounts of ROS generation, investigating the possibility of

Approaches to generate ROS as cancer therapy

The possession of higher capacity in coping with ROS induced stress might make the use of direct or indirect ROS generators possible in preferential killing of cancer cells and ameliorating the therapeutic course of the disease toward a selective method (Diehn et al., 2009). Hence, in order to inflict cancer cells with lethal damages of oxidative stress, treatment strategies trigger apoptosis by either utilizing ROS producing agents or striking of tumor cell strongholds (Benhar et al., 2002).

Targeting mitochondrial ROS as cancer therapy

Mutated cancer cells with associated disruption of mitochondrial transport chain are more likely to exhibit chronic states of metabolic oxidative stress and thus have a higher susceptibility to ROS induced apoptosis (Li et al., 2013). This escalated level of tumor cells sensitivity can be exploited for selective demolition of cancer cells (Dilda and Hogg, 2005). Mitocans are a group of anti-cancer drugs able to specifically target and destabilize cancer cells mitochondria as their achilles heel

Antioxidants in oxidative therapy against cancer

Although ROS formation is the primary mechanism of most chemotherapy drugs against cancer, unfortunately, normal tissues are also exposed to the serious side effects of these agents (Wiseman, 2005). For example, both cisplatin and anthracycline as two common drugs of current chemotherapeutic strategies can develop severe complications including nephrotoxicity, peripheral neuropathy and cardiotoxicity (Monsuez et al., 2010, Rajeswaran et al., 2008). Thus, to counteract ROS side effects and

Conclusion

ROS is a potential double-edged sword in progression and prevention of cancers (Fig. 8). Regarding to the dosage and duration of ROS and also the type of cell, all process of cell life including proliferation, or apoptosis and necrosis are specifically influenced by temporary changes in ROS concentrations and the affected signal transduction pathways. It can be concluded that cancer cells control oxidation state by balancing the involved factors at higher levels than normal cells. Thus, to

Declaration of interest

The author(s) report no conflicts of interest. The authors alone are responsible for the content of the paper.

Acknowledgments

This study was supported by Tehran University of Medical Sciences (Grant no. 22136).

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ReviewParadoxical action of reactive oxygen species in creation and therapy of cancer

Abstract

Introduction

Section snippets

Reactive oxygen species

Controversy of free radical hypothesis

ROS sources

Lipid peroxidation

Oxidant stress and inflammation

Oxidative therapy against cancer

Approaches to generate ROS as cancer therapy

Targeting mitochondrial ROS as cancer therapy

Antioxidants in oxidative therapy against cancer

Conclusion

Declaration of interest

Acknowledgments

Chem. Biol. Interact.

Peptides

Peptides

J. Biol. Chem.

Blood

Blood

Free Radic. Biol. Med.

J. Surg. Res.

J. Biol. Chem.

Lancet

Gene

Int. J. Radiat. Oncol. Biol. Phys.

Int. J. Radiat. Oncol. Biol. Phys.

Int. J. Biochem. Cell Biol.

J. Biol. Chem.

Free Radic. Biol. Med.

Am. J. Pathol.

J. Biol. Chem.

J. Hepatol.

Hepatology

Blood

Cell

J. Surg. Res.

Peptides

FEBS Lett.

Cell

Cancer Cell

Downregulation of tumor growth and invasion by redox-active nanoparticles

Antioxid. Redox Signal.

Synergism of buthionine sulfoximine and melphalan against neuroblastoma cell lines derived after disease progression

Med. Pediatr. Oncol.

Reactive oxygen generated by Nox1 triggers the angiogenic switch

Proc. Natl. Acad. Sci. USA

Reappraisal of the use of procarbazine in the treatment of lymphomas and brain tumors

Ther. Clin. Risk Manag.

Vitamin E-supplemented diets reduce lipid peroxidation but do not alter either pituitary–adrenal, glucose, and lactate responses to immobilization stress or gastric ulceration

Free Radic. Res. Commun.

Oxygen free radicals and human diseases

J. R. Soc. Health

Oxygen toxicity and reactive oxygen species: the devil is in the details

Pediatr. Res.

Inhibition of glutathione synthesis augments lysis of murine tumor cells by sulfhydryl-reactive antineoplastics

J. Clin. Invest.

Phase I study of continuous-infusion L-S,R-buthionine sulfoximine with intravenous melphalan

J. Natl. Cancer Inst.

The role of glutathione in cancer

Cell Biochem. Funct.

Arsenic trioxide inhibits human cancer cell growth and tumor development in mice by blocking Hedgehog/GLI pathway

J. Clin. Invest.

New concepts in reactive oxygen species and cardiovascular reperfusion physiology

Cardiovasc. Res.

ROS, stress-activated kinases and stress signaling in cancer

EMBO Rep.

The degradation of deoxyribonucleic acid by new tumour inhibiting compounds: the intermediate formation of hydrogen peroxide

Experientia

MicroRNAs miR-146a/b negatively modulate the senescence-associated inflammatory mediators IL-6 and IL-8

Aging

The ROS-NOX connection in cancer and angiogenesis

Crit. Rev. Eukaryot. Gene Expr.

Antioxidants, oxidative damage and oxygen deprivation stress: a review

Ann. Bot.

Dietary antioxidants and human cancer

Integr. Cancer Ther.

Targeting superoxide dismutase 1 to overcome cisplatin resistance in human ovarian cancer

Review
Paradoxical action of reactive oxygen species in creation and therapy of cancer