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 Table of Contents  
MINI REVIEW
Year : 2018  |  Volume : 4  |  Issue : 1  |  Page : 35-38

The role of reactive oxygen species in screening anticancer agents


1 Department of Health Products Cosmetics and Medical Instrument, Lanzhou Institutes for Food and Drug Control, Lanzhou, Gansu, China
2 Department of Pharmacy, Frist Hospital of Lanzhou University, Lanzhou, Gansu, China
3 Key Laboratory Breeding Base of Hu'nan Oriented Fundamental and Applied Research of Innovative Pharmaceutics, College of Pharmacy, Changsha Medical University, Changsha, Hu'nan, China

Date of Submission24-Jan-2018
Date of Acceptance14-Feb-2018
Date of Web Publication26-Feb-2018

Correspondence Address:
Assoc. Prof. Shengping Zhang
Department of Health Products Cosmetics and Medical Instrument, Lanzhou Institutes for Food and Drug Control, Lanzhou 730000, Gansu
China
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ctm.ctm_6_18

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  Abstract 


Development of anticancer agents with high efficacy and low toxicity has always been a challenge in cancer therapeutics. Reactive oxygen species (ROS) are one of the most important physiological stimuli and have been correlated with several cancer conditions. Cancer cells adapt to new higher ROS environment. Meanwhile, elevated ROS render cancer cells vulnerable to oxidative stress-induced cell death. Anticancer drugs are involved in inhibiting and suppressing cancer progression through ROS-mediated cell death. Thus, it is useful to study the level of ROS generated by anticancer agents in cancer cells, while sparing the normal cells, which is one of the target methods to study the pharmacological properties of anticancer agents. In this review, we discuss the relation between ROS and anticancer agents, as well as the application of ROS in anticancer agents' activity screening.

Keywords: Anticancer agents' activity screening, cell apoptosis, cell cycle arrest, reactive oxygen species


How to cite this article:
Xu X, Dang Z, Sun T, Zhang S, Zhang H. The role of reactive oxygen species in screening anticancer agents. Cancer Transl Med 2018;4:35-8

How to cite this URL:
Xu X, Dang Z, Sun T, Zhang S, Zhang H. The role of reactive oxygen species in screening anticancer agents. Cancer Transl Med [serial online] 2018 [cited 2018 Sep 19];4:35-8. Available from: http://www.cancertm.com/text.asp?2018/4/1/35/226172




  Introduction Top


Cancer, the second leading cause of death, is a major public health problem in the United States that needs immediate attention.[1],[2],[3],[4] In this regards, through in vitro bioassays, various synthetic or natural compounds are screened for their potential anticancer activity. The ability of such tested compounds to inhibit the growth of cancer cells under in vitro condition indicates their possible potential in vivo anticancer activity.[5] Reactive oxygen species (ROS), which includes superoxide anion, hydroxyl radical, hydrogen peroxide, singlet oxygen, and so on,[6],[7],[8] are generated during cellular metabolism, primarily in mitochondria, as well as during cellular response to external factors including bacterial invasion. Oxidative stress-induced peroxidation has been associated with human cancer.[9] Low levels of ROS has been observed in normal cells, while an increase in ROS generation has long been observed in cancer cells. Cancer cells are shown to have increased ROS levels in comparison to their normal counterparts. This is partly due to an enhanced metabolism and mitochondrial dysfunction in cancer cells.[10] Concomitantly, to maintain ROS homeostasis and evade cell death, cancer cells increase their antioxidant capacity.[11] Cancer cells in advanced stage tumors frequently exhibit multiple genetic alterations and high oxidative stress, suggesting that it might be possible to preferentially modulate the development of these cells by controlling their ROS production.[12] However, ROS act as a double-edged sword in cancer cells, on the one hand, ROS can promote pro-tumorigenic signaling, facilitating cancer cells proliferation, survival, and adaptation to hypoxia, on the other hand, ROS can promote antitumorigenic signaling and trigger oxidative stress-induced cancer cell death.[11] Recent studies suggested that the biochemical activity of ROS on cancer cells could be exploited for therapeutic benefits.[13] Effects of anticancer agents on ROS have been reported previously.[14] These anticancer agents can induce ROS pathway activation which results in S-phase cell cycle arrest, but N-acetylcysteine (NAC), a ROS inhibitor, could effectively abrogate the S-phase arrest. Anticancer agents also block cancer cells at the S-phase by the downregulation of CDK1, CDK2, Cyclin A, and Cyclin B1 through ROS pathways.[15] Caspases are crucial components of the apoptotic machinery in various cells, the activation of which is a central event in the process of apoptosis. Anticancer agents dramatically increase the expression of cleaved caspase-3, 8, 9, which is almost completely abolished by NAC. These findings indicate that anticancer agents induce apoptosis of cancer cells through the ROS-dependent activation of caspases.[15] Many anticancer drugs promote oxidation of the tumor; to induce tumor cell death through increased ROS levels and to inhibit intracellular antioxidant enzyme system. Of course, there are also many pathways involved in the downstream of ROS and oxidative stress-induced cell activates. Hence, ROS exert oxidative stress and induce cell death through various signaling pathways, such as proliferation (protein tyrosine phosphatases, mitogen-activated protein kinase, and phosphoinositide 3-kinase); ROS homeostasis and antioxidant gene regulation (thioredoxin, peroxiredoxin, Ref-1, and Nrf-2); mitochondrial oxidative stress, apoptosis, and aging (p66Shc); iron homeostasis through iron–sulfur cluster proteins (IRE–IRP); and so on.[16] In this review, we discuss the anticancer role of ROS, including the induction of either cell cycle arrest or apoptosis through its signaling pathways, and the application of ROS in the anticancer agents' activity screening.


  Anticancer Agents Exert Anticancer Activity Via Ros Signaling Pathways Top


The role of reactive oxygen species signaling pathways in cancer cell-division cycle

The cell-division cycle consists of four phases: G1 phase, S phase, G2 phase, and M phase. Recently, it has become clear that ROS influences cell cycle progression.[17] ROS can positively influence tumor cell proliferation and mediate cytotoxicity, while increase in ROS can reduce cancer cells proliferation by inducing cell cycle arrest.[18] Recent studies found that anticancer agents could increase intracellular accumulation of ROS in cancer cells[19] and induce cancer cell cycle arrest, which can be abolished by NAC, a ROS inhibitor.[20],[21] For instance, bortezomib induced an increase in intracellular ROS and on treatment with the ROS scavenger NAC a decrease in the number of cells in G2-M phase was seen.[22] Similarly, daidzein retards G1/S cell cycle transition by regulating intracellular ROS in hepatoma cell line (BEL-7402).[23] The study, along with other studies, also showed that ROS often controlled ubiquitination through phosphorylation, and that the process of phosphorylation is influenced by ROS.[12],[17],[23] In general, ROS affect cell cycle progression by regulating gene transcription of cell cycle regulatory enzymes such as cyclins (CDKs and CKIs), while at the same time the course of transcription stimulates ROS production.[15] The produced ROS can influence cell cycle progression through affecting phosphorylation and ubiquitination of cell cycle regulatory enzymes.[24]

Reactive oxygen species signaling pathways induce cancer cells apoptosis

Cell apoptosis represents one of the hallmarks of the tumor cells death,[25] which can be triggered by a variety of stimuli, including chemotherapeutic agents. Apoptosis is also related to activation of specific proteases, termed caspases. Apoptotic cell exhibits distinct morphological and biochemical features, such as chromatin condensation, membrane surface blebbing, DNA fragmentation, and so on. Deregulation of apoptotic process may lead to cancer cell formation and proliferation. ROS is generated within the cells during metabolic reactions, and hence its basal level is very high in cancer cells.[26] ROS is targeted by few anticancer agents to bring about cancer cells apoptosis and inhibit proliferation.[27],[28],[29] The aim of screening anticancer agents is to assess their ability to kill cancer cells, mainly through apoptosis, without harming normal cells. This ability to kill cancer cells is through contributing a novel redox system of regulatory control, superimposed on established growth signal pathways that mainly include tyrosine phosphorylation, some apoptosis regulating proteins, and the tumor necrosis factor/nerve growth factor receptors family.[30] However, other mechanisms, such as ROS generation, appear to be equally important. For instance, the antioxidant NAC blocks apoptosis in some tumor cells, but anticancer agents induce apoptosis in some tumor cells.[31] Some published studies over the past years, both in cell culture and animal models, have demonstrated the ability of anticancer agents to act on ROS in inducing apoptosis in cancer cells.[32]


  Reactive Oxygen Species in Screening Anticancer Agents' Activity Top


The level of ROS generated by a target compound may decide if it can be translated to clinical application. Almost all types of cancer cells show abnormally elevated levels of ROS as well as equally elevated expression of antioxidant agents to neutralize the ROS.[33] The presence of ROS creates an environment of higher intrinsic oxidative stress. All therapeutic approaches, either conventional or alternative, target either one or more of these acquired properties by disturbing the redox status of the cancer cells, to inhibit proliferation or to cause cell damage and cell death.[34] Anticancer agents are shown to induce apoptosis in human cancer cells, both in vitro and in vivo, through promoting ROS signaling pathways,[35] which demonstrate their potential in clinical treatment. Anticancer agents can not only directly increase ROS generation but also weaken the antioxidant defense system of cancer cells, leading to cell cycle arrest and cell apoptosis. Hence, ROS are regarded as the target of the anticancer agents in cancer therapy.[30] On the contrary, this makes the cancer cells vulnerable to agents that act as pro-oxidants and increase the existing ROS levels, thereby disturbing the ROS balance and tipping the cell machinery toward apoptotic cell death. Most conventional chemotherapeutic drugs induce cytotoxicity by raising intracellular ROS levels but pose the problem of nonselective killing of normal cells and development of drug resistance due to prolonged exposure.[36],[37] To assess the potential antiproliferative activity of anticancer agents, 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide assay is used. Flow cytometry assays are used to examine the effects of anticancer agents on cell cycle and cell apoptosis. Western blot assays and real-time polymerase chain reaction are performed to confirm the apoptosis-associated signaling pathways caused by ROS generation, and ROS formation was monitored by fluorescence microscopy using the superoxide indicator dihydroethidium staining.[38] Recently, several in vitro and in vivo models have been developed to study the role of ROS in the development of cancer, and to explore the utilities of ROS-mediated mechanisms in prevention and therapeutics of cancer diseases, which will be useful in anticancer agents' activity screening.[39],[40] Previously reported effects of anticancer agents on ROS are summarized in [Table 1].
Table 1: Summary of the published works about anticancer agents act on reactive oxygen species

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  Conclusion Top


In summary, an overproduction of ROS is observed in cancer cells, whereas it is underexpressed or absent in normal cells. Cancer cells depend heavily on the antioxidant defense system, and anticancer agents further increase cellular ROS levels by direct ROS generation. ROS generation in cancer cells contributes to the biochemical and molecular changes necessary for the tumor initiation, promotion, and progression, as well as tumor resistance to chemotherapy, thereby activating various ROS-induced cell death pathways, or inhibiting cancer cell resistance to chemotherapy is an alternative approach. Such results can be achieved using anticancer agents that either increase ROS generation, or inhibit antioxidant defense, or even a combination of both. In fact, some anticancer drugs used clinically or anticancer agents under clinical trials induce cancer cells death through enhancing ROS generation and/or impeding the antioxidant defense mechanism.[10] In anticancer drugs screening, the elevation of ROS by anticancer agents can be used to achieve the selective killing of cancer cells, which is crucial in cancer cells apoptosis and death pathway. Hence, detecting the ROS levels is an effective method to evaluate their efficacy and attain our goal of screening more potent anticancer agents while studying the anticancer activity of targeted compounds.[41],[42],[43],[44],[45],[46],[47],[48],[49]

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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