|
 
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| REVIEW ARTICLE |
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| Year : 2014 | Volume
: 10
| Issue : 4 | Page : 811-818 |
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Reactive oxygen species as mediator of tumor radiosensitivity
Renu Dayal, Amrita Singh, Anubhuti Pandey, Kaushala Prasad Mishra
Division of Life Sciences, Research Centre, Nehru Gram Bharati University, Allahabad, Uttar Pradesh, India
| Date of Web Publication | 9-Jan-2015 |
Correspondence Address:
Kaushala Prasad Mishra
Division of Life Sciences, Research Centre, Nehru Gram Bharati University, Allahabad - 211 002, Uttar Pradesh
India
 Source of Support: None, Conflict of Interest: None  | Check |
DOI: 10.4103/0973-1482.146073
In normal functioning of the cell, there is a balance between generation and neutralization of reactive oxygen species (ROS) by endogenous cellular defense machinery. Low levels of ROS inside the cells are required for normal functioning of the cell, which regulate signaling mechanisms involved in mitosis and apoptosis; excess of ROS production may cause oxidative stress leading to damage in vital cellular molecules, namely cytosolic lipids, proteins, and DNA. In the situation of intracellular redox imbalance, molecules of cells are altered by ROS leading to pathogenic state. It is to be noted that ROS is not only known to be involved in tumor induction and progression processes but also enhances tumor cell radiosensitivity. The level of ROS-mediated oxidative stress is linked to cellular radiosensitivity. In general, cancer cells exhibit high levels of ROS, which forms a target for selectively killing them by radiation. In this paper, we have reviewed how oxidative stress determines the radiosensitivity of tumor cells involving ROS in the mechanism of radiation induced tumor cell killing. It is suggested that radiation-induced ROS play a key role in the mechanism of tumor cell killing by altering the signaling network and triggering of apoptosis. Furthermore, it is pointed out that combined use of plant-derived antioxidants and radiation enhance overproduction of ROS in tumor cells leading to enhanced radiosensitivity, which may find practical applications in clinic. 活性氧粒子作为肿瘤辐射敏感性的介质
摘要
在正常运作的细胞中，活性氧粒子（ROS）的生成和中和是由内源性细胞防御机制来达到平衡的。在细胞的正常运作中，低水平的ROS是所需的，它参与调节有丝分裂和细胞凋亡的信号传导机制；过量的ROS可引起氧化应激导致细胞分子的损伤，即细胞内脂质，蛋白质和DNA的损伤。在细胞内氧化还原失衡的情况下，ROS将改变分子细胞导致致病状态。值得注意的是，ROS不仅是参与肿瘤的诱导和进展过程，而且提高了肿瘤细胞的放射敏感性。ROS介导的氧化应激的水平与细胞的放射敏感性有关。一般来说，癌细胞表现出高水平的ROS，因此可以选择放射治疗来杀伤它们。在本文中，我们回顾了氧化应激决定肿瘤细胞的辐射敏感性，包括ROS在诱导辐射杀伤肿瘤细胞中的机制。这表明辐射诱导的ROS在肿瘤细胞通过改变信令网和触发细胞凋亡杀伤机制中发挥重要的作用。此外，还有一点也被指出，即联合使用植物来源的抗氧化剂和辐射增强生产过剩的ROS将导致肿瘤细胞的放射增敏，这可见于临床实际应用中。
关键词：抗氧化剂，氧化应激，辐射，活性氧，肿瘤的放射敏感性，肿瘤毒性
Keywords: Antioxidants, oxidative stress, radiation, reactive oxygen species, tumor radiosensitivity, tumor toxicity
How to cite this article:
Dayal R, Singh A, Pandey A, Mishra KP. Reactive oxygen species as mediator of tumor radiosensitivity. J Can Res Ther 2014;10:811-8 |
| > Introduction | |  |
Radiotherapy is an important treatment modality of cancer involving ROS as key intermediate in tumor toxicity. Treatment of cancer by radiation is a most common modality; however, the outcome is limited as healthy tissues in neighborhood of target tumor cells are adversely affected. Radiation-induced inhibition of tumor growth depends on the maintenance of balance between cell division and apoptotic death. When ROS level rises beyond a tolerable limit inside tumor cell, signaling network alters and apoptosis process begins leading to toxicity. Therefore, developing cancer treatment strategy consists of utilization of ROS-mediated induction of apoptotic signaling in tumor cells. Treatment of cells with drugs or ionizing radiation (IR) or their combinations that can enhance intracellular ROS would prove effective in causing cytotoxicity. When ROS are produced, they readily react with membrane lipids and proteins resulting in change of membrane permeability, proteolytic degradation; with DNA causing damage and genomic instability eventually inducing radiosensitivity and apoptosis. [1],[2] In radiotherapy procedure, the objective is to kill tumor cells but normal tissues neighboring the target cancer cells are also damaged by the delivered doses of IR. [3] Besides, prolonged exposure or high radiation dose may produce several undesirable health effects such as radiation sickness and skin diseases. [4] To mitigate these effects, conventional drugs are employed to protect cells from radiation damage. These drugs mainly belonging to antioxidant (AO) category called radioprotectors prevent damage by different mechanisms. One possible mode of action is presumably to initiate apoptosis resulting in enhanced sensitivity of tumor cells to radiation and afford protective effect to normal cells at low radiation doses. The first evidence of radioprotector was in the form of cysteine derivatives by Patt et al. (1949), which opened a new field of research in radiotherapy. Subsequently, a large number of compounds and their analogs have been tested for their ability as radioprotector. [5] The major molecular mechanisms of conventional radioprotectors such as aminothiol, amifostine (WR-1065) are suggested to involve free radical scavenging, depletion of oxygen near DNA, enhancement of biochemical repair processes, or combination of these mechanism in normal cells. [6],[7],[8],[9] However, the use of these compounds suffers from some undesirable effects such as nausea, vomiting, hypotension, and allergic reactions apart from high cost, short-time impact, and failure to provide long-term protection. [7],[10],[11] Due to unwanted side effects, most of the conventional radioprotectors find limited use in practical applications. Many herbal compounds possess AO properties and offer a more potent but less toxic effects on cellular systems. In the past few years, researchers have laid greater emphasis on the use of plant and plant-derived products (e.g. herbals) in tumor therapy due to its effectiveness and compatibility. A number of pharmacological agents have been tested for their tumor radiosensitivity and reduced side-effects in radiotherapy practice. Evidence has accumulated to suggest that in combination treatment protocol, natural AOs have ability to preferentially sensitize tumor cells to radiation but cause no damage to normal cells. [12],[13],[14],[15],[16] Studies on herbals by our research group and others have provided compelling evidence on their different modes of action under different cytosolic status. [12],[13],[14] It is therefore important to develop strategies to increase sensitivity of tumor cells to radiation in combination with new tumor-specific cytotoxic herbal agents. It is known that cancer is resultant of shutting off of the apoptosis pathway that disturbs normal balance of cell regeneration and death. One of the potential approaches to achieve tumor toxicity is to increase the oxidative stress level of tumor cells beyond their tolerance limit. Because cancer cells are already stressed, increasing ROS level by the action of some external source would lead to failure of in-built defense machinery of the cancer cells, causing DNA damage that might lead to apoptotic death. In the following sections, we have discussed the mechanisms underlying these processes.
| > Ros-Mediated Oxidative Stress | | |
Reactive oxygen species consist of radicals of oxygen origin. Low doses of radiation (<500 m Gy) are known to affect cellular signaling, whereas high doses (a few Gy to kGy) are needed for toxicity/damage of cells. [17] Reactive oxygen species are generated inside cells by action of IR, which are implicated in both induction and treatment of cancer. No doubt, it is regarded as double-edged sword in cellular biochemical processes. Reactive oxygen species are continuously produced by the living system as a result of electron leakage from the mitochondria during electron transport chain (ETC) reaction. However, the toxic levels of ROS are immediately detoxified by endogenous AO defense system. In case of failure of AO defense and/or overproduction of ROS, cellular redox balance gets disrupted creating an environment of oxidative stress. The fate of oxygen during respiration in mitochondrial ETC is explained in [Figure 1]. The coenzyme Q 10 (CoQ 10 ) in mitochondria under certain conditions (pathological conditions) transforms as a superoxide generator and contributes to ROS formation. [18] Enzyme oxidase in endoplasmic reticulum generates superoxide. Xanthine oxidase is also indirectly involved in ROS generation. [19] | Figure 1: Diagrammatic representation of the fate of oxygen during respiration in mitochondrial electron transport chain. (a) Normal mitochondrial status (b) Pathological condition (during electron leakage)
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ROS and genomic instability
ROS poses threat to various vital cellular molecules including DNA, cell membrane, lipids, proteins and mitochondria if not detoxified. [18],[19],[20] Mitochondria is the primary site of free radical generation and perhaps the foremost targets of radiation-induced damage along with cell membrane. The mitochondrial ROS released into the cytosol contributes to significant damage in macromolecules that may cause genomic instability. Parameters such as DNA repair system, cell cycle checkpoints, mismatch repair and some enzymes control and regulate the maintaining of genomic integrity of stressed cells. [21] It was suggested that deregulation of these parameters may cause chromosomal instability. [22],[23] Hopefully, discovery of the cause and specific role of genomic instability in cancer will yield more effective chemotherapy strategies that take advantage of this unique characteristic of cancer cells. [22]
Initiation and progression of tumor
Studies have shown that ROS such as hydrogen peroxide, hydroxyl radical activate nuclear factor kappa B (NF-κB), pro-oncoproteins (Bcl and Bax) and induce double-stranded DNA breaks. [21],[24] DNA damage leads to cell transformation, telomerase dysfunctioning, which, if not repaired, may cause mutation and tumor formation by various signaling cascades. Reactive oxygen species-generated oxidative stress mutates p53 checkpoints, cyclin, cdks, leading to abnormal functioning of the cell cycle. Activation of telomerase, enzyme that synthesizes telomeric DNA and induces p53 mutation, is proposed to be an essential step in tumor cell immortalization and cancer progression. [25] Transformed cells resist apoptosis leading to cellular immortalization. As a result, cell cycle proliferation dominates cell death. Alteration in these cancer-relevant genes and proteins transforms normal cells toward malignancy, hence represent good therapeutic targets. [22]
ROS and apoptosis
Mechanisms of radiation-induced cell death are influenced to varying degrees by cell and tissue-type-specific factors. Reactive oxygen species-mediated cell killing may induce death through necrosis, apoptosis, mitotic cell death, autophagy and permanent cell cycle arrest. Recent trend of cancer therapy involves the down-regulation of the strong and defensive AO system of cancerous cells through augmenting ROS concentration-mediated oxidative stress. [26] Several evidences suggest that transformed cells can be selectively killed by exogenous ROS-mediated treatments. [27],[28] Generation of free radicals during radiation exposure and lipid hydroperoxide triggers DNA damage and apoptosis. [27],[29]
It is well known that cancer is shutting of apoptosis; therefore, inducing apoptosis is not only the most effective and common defense against cancer but also a phenomenon that offers an opportunity to accelerate tumor elimination. The process of programmed cell death is characterized by distinct morphological characteristics and energy-dependent biochemical mechanisms. Characteristic morphological changes of apoptotic cell include cell shrinkage, pyknosis and extensive plasma membrane blebbing leading to the formation of apoptotic bodies, which are subsequently phagocytized by macrophages. Cysteine-dependent aspartate-specific proteases-8 (Caspase-8) regulates tumor necrosis factor (TNF) alpha-induced epithelial necroptosis and terminal ileitis. [30] Caspases are typically activated during the early stages of apoptosis; and they further activate other degradative enzymes that initiate DNA cleavage in the nucleus.
| > Ros in Radiotherapy | | |
Radiotherapy is one of the most reliable and widely used treatments for tumor. Therapeutic approach aims to protect normal cells along with ROS-mediated eradication of tumor cells. Ionizing radiation exposure of target organs generates ionization in structural cellular molecules. [31] High level of ROS produced by radiation results in oxidative stress that destabilizes cells integrity. The persistent oxidative stress in cancer cells apparently sensitizes them to undergo apoptosis by anticancer drugs, which often generate ROS. That is, compared to normal cells, cancer cells are more susceptible to being killed by radiation-generated ROS because the cancer cells are already near a threshold for tolerating ROS. [28] Reactive oxygen species-induced cell death may be either direct or indirect. Highly reactive species cause a cluster of lesions within the DNA strand that are difficult to repair and lead to cell death. [2],[32] Besides DNA damage, other major target of radiation and ROS are believed to be the membranes of cells and organelles. It is observed that membrane lipids are easily peroxidized by ROS produced by IR, which causes structural and functional impairment that may contribute to cell cycle arrest and apoptosis. [2],[33] Indirect effect involves altered cellular homeostasis and modifying signaling pathways ultimately leading to apoptosis. [32] It is this property of ROS that makes it worth to be used for sensitization of tumors during radiotherapy with reducing probability of normal cell damage. Radiation damage that occurs in clusters matching the size of the DNA strand may be more effective cellular damage. The produced ROS-mediated stress signaling is activated in tumors/cancer cells via irradiation. The magnitude of three important mitogen-activated protein kinase MAPK (ERK, JNK and p38 MAPK) up-regulated by ROS might determine whether tumor cell proliferates, undergo cell cycle arrest and apoptosis. [28] Irradiation may cause damage to rapidly dividing cells normal tissues sideways with cancer/tumor. Also, many tumors are slow dividing as they spend long time in S-phase/interphase, henceforth they get much time to repair the damaged DNA. As a consequence they display resistance toward irradiation at optimum dose levels. Hence, radiosensitizers are looked for to make slow dividing tumors sensitive to irradiation along with protection of healthy cells. Radioresistance of tumor cells is multifactorial that may include cell cycle phase, gene expression and oxygen availability. Considering the importance of radiosensitization of tumor cells, researchers have focused interest toward AO-mediated targeted radiotherapies. Probable biological effects of AOs and IR-mediated ROS on cells during radiotherapy are schematically shown in [Figure 2]. There may arise two kinds of radiation responses on tumor cells: Either they are readily sensitized by radiation exposure or exhibit resistance. Radiotherapy alone might not be effective on radioresistant tumor cells. It has been suggested that in the presence of certain AOs tumor cells are radiosensitized and resistant tumor cells too respond to radiation killing mostly by triggering the ROS-mediated induction of apoptosis | Figure 2: Schematic diagram showing probable biological effects of ionizing radiation (IR)-mediated reactive oxygen species (ROS) on tumor cell alone and in combination with anti-oxidants (AOs). (i) They either may readily sensitize toward radiation exposure or (ii) exhibit resistance to it. Radiotherapy alone might not be effective on radioresistant tumor cells. In the presence of radiosensitizing agents such as antioxidants, tumor cells are radiosensitized and resistant tumor cells too respond to radiation killing mostly by triggering the ROS-mediated induction of apoptosis
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ROS-mediated tumor radiosensitivity
Not all tumor cells are equally sensitive to IR-induced cell damage. In general, rapidly dividing cells are relatively more sensitive to ROS-induced oxidative damage as compared to those that are slow dividing. The pathological processes of injury to normal tissues begin immediately after irradiation, but the clinical and histological features may appear after weeks, months, or even years after treatment. [34],[35] The sensitivity or resistance of tumor cell toward ROS depends on cell cycle phases, endogenous AO levels, oxygen availability, signaling pathways, etc. [Figure 3] briefly explains ROS-mediated phenomenon of radioresistance and sensitivity during cell cycle. Hypoxia is also a critical micro-environmental factor in multiple myeloma. Hu et al. (2013) suggested that targeting hypoxic multiple myeloma cells may improve multiple disease parameters. [36] Experimental evidences suggests that post-radiogenic MAPK pathway activation and vascular endothelial growth factor (VEGF) release results in reduced tumor cell response. [37],[38] | Figure 3: Schematic diagram showing endogenous AO-dependent radiosensitivity of various phases of cell cycle toward irradiation. Differential radiosensitivity, which is commonly observed during various phases of the cell-cycle, is related to a difference in the levels of endogenous antioxidants such as SH-compounds and their derivatives (cysteamine, glutathione, and others). Mitotic cells, which are most radiosensitive, have the lowest levels of SH-containing AOs and that S-phase cells, which are the most radio resistant, have the highest level of these endogenous AOs
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Toxicity to sensitive cells
Sensitivity or resistance of a cell toward radiation largely depends on specific phase of cell cycle in which targeted cell is present at that particular time of exposure. Cells of M phase and G2 phase are most sensitive to IR as compared with S phase. It is because the chromosomes are lined up on the spindle and are directly exposed to radiation. In addition, differential radiosensitivity is also related to a difference in the levels of endogenous AOs (SH-containing group), as shown in [Figure 3]. Various studies showed that mitotic cells, which are most radiosensitive, have the lowest levels of SH-AOs and that S-phase cells, which are the most radioresistant, have the highest level of these compounds. [39],[40] Reactive oxygen species-induced damage is difficult to repair targeted tumor cells, which may die or function aberrantly. Researchers, therefore, suggest synchronization of cell cycle under these two sensitive phases of cell cycle for complete eradication of tumor. [41],[42]
ROS and resistance
Whatever treatment we employ during clinical stages, at some point of treatment cells usually overcome the toxic effects of drugs and show resistance toward them. Such cells are categorized as radioresistant cells, capable to repair the damage. Stem cells and their counterpart cancer stem cells (CSCs) are examples of such resistant cells exhibiting resistance to radiation exposure because of low levels of intrinsic ROS and enhanced endogenous defenses. [43] Studies have shown that intrinsic radiosensitivity of cells was directly correlated with radiation-induced ROS and cell cycle regulation. [41],[42],[44],[45] Correspondingly, less the level of ROS in tumor cells, more radioresistant (or less radiosensitive) they can be. [28],[43] Diehn and coworkers (2009) suggested that low ROS levels in CSCs are associated with increased expression of free radical scavenging systems. In addition, they advocated that depletion of ROS scavengers in CSCs markedly decreases their clonogenicity and results in radiosensitization. [43]
Recently, Affolter et al. (2012), reported increased radioresistance in epithelial cancer by compensatory up-regulation of MAPK and PI3K pathways. [37] Cells that spend a long period of time in interphase will be able to repair a significant portion of radiation-induced DNA damage before they enter mitosis, hence survives longer. On the other hand, DNA of S-phase replicates in the presence of duplicated DNA strands that provides a useful template for repair. Up to this point, only high radiation doses can affect the S phase. Thus, rapidly dividing tumor cells present in S phase require high biodosimetry. However, cycle arrest of normal cells at the S/G2M phases of the cell cycle has importance form radioprotection point of view. [43],[46]
Future research strategies
The new approaches to improve radiotherapy largely concern in achieving the increased tumor cytotoxicity with minimal or null toxicity to normal cells. The ROS level can be increased by inhibiting endogenous AOs such as superoxide dismutase (SOD) through ROS-inducing agents like AOs, IR and hyperthermia. In addition, cell membrane protein and lipids form significant targets for ROS attack. Molecular changes in these cellular moieties increase the risk of cell death through apoptosis or necrosis. We propose such proteins and lipids to be the radiation centers specifically present in transformed cells. Evidently, targeting these radiation centers by oxidative damage process may accelerate radiosensitizing effect with radiation and drugs acting through modulation of membrane-associated events involved in the mechanism of induction of apoptosis.
An alternative promising strategy is the combined use of radiosenstizers together with radiation exposure. In this context, AOs hold great potential to be effective radiosensitzers. In our laboratory, we are searching for AOs from plant sources with potential to initiate apoptosis in tumor cells without affecting cellular integrity of normal cells. In many recent studies, including results from our laboratory, certain AOs have been shown to enhance the ROS-mediated susceptibility of tumor cells to radiation. [12],[13],[15],[16],[39],[42],[45],[46],[47],[48]
Considerable active research has been devoted to either refining advancements on radiation treatment or to develop compounds that preferentially sensitize tumor cells during irradiation. [12],[13],[15]
| > Antioxidants, Ros and Toxicity | | |
There is an urgent need to identify a drug that is apoptosis inducer in tumor cells. To overcome drug and/or radiation resistance, proper strategies have to be devised to up-regulate endogenous ROS threshold predisposing tumor cells to follow apoptosis pathway by external therapies. Turning cells vulnerable to apoptotic mechanism would help reduce the therapeutic radiation dose and thus reducing the damage to normal cells in neighboring targeted area. For sensitization of such tumor cells, herbal AO drugs are proving remarkable candidates. It has been reported that herbal composition like Triphala displays differential toxicity to normal and tumor cells. In a phase I clinical study by Phetkate and coworkers, Triphala has demonstrated significant increase in cytotoxic T lymphocytes and natural killer cells. [49]
One of the suggested mechanisms to treat tumor cells by a particular radiosensitizer before irradiation consists of synchronizing tumor cells to a radio-sensitive phase of cell cycle. [50] Our aim should be to search for protocols to increase the stressed condition of the cells by inducing ROS from outside sources to the level where its in-built defense fails to cope up with excess of ROS. As a consequence of which cells will die inevitably by apoptotic pathway.
Herbals enhance tumor radiosensitivity
In the past few years, use of plant and plant products (herbals) has gained remarkable status as natural medicinal resource in almost all fields of medicine due to its effectiveness and reliability. Radiotherapy for treatment of cancer is not an exception. The drawbacks of conventional radiosensitizers necessitated the search for new plant-based radiosensitizers/radiomodulators. Unacceptable side-effects of chemical radioprotectors made researchers to look toward medicinal plants as potent radiomodulator. Herbal AOs and their derivatives like flavonoids, phenolics have immense potential as radiosensitizers, [51],[52] which can be toxic for tumor cell together with synchronized role as radioprotector for normal cell. For instance, concurrent use of plant-derived alkaloid etoposide appears to be one of the most efficient concurrent treatment in combination with radiotherapy. [53],[54] It is supposed to increase radiosensitivity of cancer cells that divide more quickly than normal cells. However, more likely normal cells are also affected by etoposide. Furthermore, they fail to discriminate cytosolic status between tumor and normal cells, hence unable to protect rapidly dividing normal cells neighboring the radiation targeted area. Therefore, search of potent herbal is urgent and warranted to minimize the severe side effects of conventional drugs during and after radiotherapy.
It is admitted that to date effective radioprotector having null or least toxicity to normal cells at optimum protective doses does not exist. Most of available ones are not much effective at optimum protective dose levels, hence practically require high dose or are effective only when administered before irradiation. [55] Cumulative research findings suggest that indigenous medicinal plants and their bioactive compounds have immense potential for the prevention and treatment of cancer. Some of the plants or their herbal compositions were found to be effective in inhibiting MMPS, NF-κB translocation and lipid peroxidation. [28],[32] It was found that pretreatment of various extracts before irradiation not only reduced the tumor volume, but also AO level (GSH, MMPS, CAT, etc.) of tumor cells. It also accelerated the recovery of AO level of normal tissues to average redox levels along with strong free radical scavenging activity. [28],[32] It has been reported that herbals, like Triphala, Hippophae leaves, Curcuma, display differential toxicity for normal and tumor cells. [12],[14],[15],[16] Bioactive compounds of these and many more indigenous herbals viz. gallic acid, flavones, curcumin are capable enough to enhance sensitivity of tumor cell toward irradiation and radioprotection to normal tissues. [12],[14],[15],[51],[56],[57] From these findings, we can portray the probability that AOs up-regulate endogenous defense machinery of normal cell toward irradiation induced stress like enhanced intracellular SOD or GSH.
Pharmacological properties of herbs and their derivative enable them to distribute differentially or activate and to have selective metabolic effects among tumor cells and normal tissues. [12],[15],[58] Furthermore, about three-fourth of the compounds used in chemotherapy are majorly derived from plants like taxol, vinca alkaloids. [55]
Various phytochemicals possess potential to accelerate oxidative damage or ability to synchronize the tumor cells to a radiosensitive phase of cell cycle thus enhanced killing. [50] Several investigations suggested that AOs inhibits repair of radiation-induced damage in cancer cells and therefore damage in cancer cells is further enhanced by the continued presence of AOs after irradiation. [28],[39],[45] Prasad (2004) suggested that high expression of c-myc and H-ras oncogenes increases radioresistance of tumor cells, whereas high-dose AOs reduces the expression of these oncogenes and therefore administered particular AO before irradiation may enhance the sensitivity of these cells to radiation. [45]
Several in vitro reports have appeared including the results from authors laboratory that tumor cells were sensitized to radiation in the presence of certain non-dietary AOs, such as Triphala, biochanin A, eugenol and ellagic acid. [12],[42],[46],[50] We are inclined to believe that AOs from herbal sources have the potential to identify these redox status differences of tumor cells compared with the normal cells and cause radiosensitivity involving ROS generation.
Herbals mediated radiosensitization of tumors toward irradiation is suggested to involve up-regulation of apoptotic genes with simultaneous down-regulation of growth regulatory pathways, transcription factors NF-κB, COX2, Akt, anti-apoptotic proteins, growth factor receptors and multidrug-resistance proteins. [26],[59] On the contrary, these phytochemicals keep normal cells unaffected during irradiation. [12],[46] Additionally, when radiation acts on a cell, it is not necessary that it will target all the organelles. It rather targets on specific radiation centers (certain/particular transformed lipids or proteins) that are sensitive toward radiation exposure. Hence, we propose that AOs with herbal background have the potential to identify these specific reaction centers of tumor cells with changed cellular environment. Thus, they specifically sensitize those tumor cells with protecting or at least not affecting normal cells. However, noteworthy results obtained at preclinical phases may not have significance at clinical stage due to poor water solubility, low absorptivity, local gastrointestinal mechanism, [60] and low bioavailability of bioactive compound [60],[61] of interest. Correspondingly metabolism activity, for instance availability of specific enzymes, gut bacteria, absorption capacity also varies from person to person. For instance, Vareed and coworkers showed that the absorbed curcumin after oral dosing in humans is detected as glucuronide and sulfate conjugates in plasma. [62] In another work conducted by Shia et al (2008)., we observe that fisetin and 7-OH-flavone were rapidly and extensively bio-transformed into their sulfate/glucuronide, whereas 5-OH-flavone was exclusively metabolized to glucuronide. [63]
Taken together understanding of mechanism of action of specific herbal bioactive compound such as manifestation of differential cellular effect, their pharmacokinetics in the living system and their synergistic effect to trigger-specific signaling pathways may help to develop ideal/efficient drug for improving cancer radiotherapy. Interfering with oncogenic signaling pathways like MAPK, ERK, AKT, or cell cycle arrest seems another possible mechanism of tumor cell death by AOs. The future perspectives lie in identifying more such compounds and elucidating their mechanism of action.
| > Conclusion | | |
Reactive oxygen species-mediated oxidative stress effects vary from cancer promoter to inhibitor. When in excess, it may disturb redox balance, cause mitochondrial change, induces lipid peroxidation, causing membrane and DNA damage. Although, ROS-mediated cell damage to infected cells is productive but subsequent damage to normal cells is a matter of concern. Furthermore, if not counteracted by apoptosis, it leads to cell transformation and subsequent tumor progression. Oxidative stress is directly related to radiosensitivity of cells. Therefore, it is highly warranted to identify the risk-benefit ratio of ROS in normal and tumor cells. Success of radiotherapy depends on its ability to selectively induce apoptosis in tumor cells by sparing normal cells. Tumor cells being in higher oxidative state provide a selective target for radiation and therapeutic drug action. It is emphasized that radiation generated excess ROS in tumor cells may drive them to apoptosis resulting in increased radiosensitivity. Normal cells may be spared because of low level of intrinsic ROS, which may be inadequate to trigger apoptosis.
Consequently, it is necessary to search for agents that can trigger and modulate the ROS-mediated damage in tumor cells, which ultimately causes cell death. Exogenously inducing ROS increases the oxidative stress condition of the tumor cells that are already under stress, which increases the probability of collapsing their endogenous defense system, predictably leading to cell death. It seems possible that targeting ROS-sensitive molecular centers of tumor cells may enhance radiosensitization at lower IR doses. Herbals are potential candidates for inducing ROS-mediated synergistic effect to sensitize radioresistant and CSCs to lower doses of IR. Cumulative use of herbals along with radiation also ensures protection to normal cells.
| > Acknowledgment | | |
Ms. Renu Dayal, recipient of Rajiv Gandhi National Fellowship from University Grant Commission, New Delhi, India; deeply acknowledge the financial support for doctoral research work. With core of heart the authors are thankful to Dr. R.P. Ojha for his valuable guidance.
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