Edited by: Xue-Jun Sun, Taishan Medical College, China
Reviewed by: Wenwu Liu, Second Military Medical University, China; Sheng Chen, Zhejiang University, China
*Correspondence: Banasri Hazra, Department of Pharmaceutical Technology, Jadavpur University, Kolkata 700 032, India. e-mail:
This article was submitted to Frontiers in Ethnopharmacology, a specialty of Frontiers in Pharmacology.
This is an open-access article distributed under the terms of the
Treatment of cancer often requires exposure to radiation, which has several limitations involving non-specific toxicity toward normal cells, reducing the efficacy of treatment. Efforts are going on to find chemical compounds which would effectively offer protection to the normal tissues after radiation exposure during radiotherapy of cancer. In this regard, plant-derived compounds might serve as “leads” to design ideal radioprotectors/radiosensitizers. This article reviews some of the recent findings on prospective medicinal plants, phytochemicals, and their analogs, based on both
Cancer is now the third leading cause of death worldwide, with an estimated 12 million new cases and 7.6 million cancer deaths reported in American Cancer Society (
Application of ionizing radiation, over and above surgery, and chemotherapy, has been the treatment of choice in case of solid malignancies (Kinsella,
Moreover, co-administration of radiation (delivered in the range of 40–80 Gy) along with the chemotherapeutic regimen might aggravate these complications (Curry and Curran,
The exposure to radiation would primarily generate intracellular reactive oxygen species (ROS, viz., superoxide and hydroxyl radicals), which in turn would lead to DNA strands breaks and conformational alterations of biomolecules (Halliwell and Gutteridge,
Screening and testing of compounds from natural as well as synthetic sources have been carried out over the last few decades in order to find effective radioprotectors capable of inhibiting radiation damage not only during radiotherapy of cancer patients, but also to healthy individuals undergoing occupational and accidental exposures to radiation (Stone et al.,
The global search for naturally occurring phytochemicals as potential radiotherapeutic agents has unearthed a host of plant products broadly categorized as (i) “radioprotectors”- to ameliorate the undesired damages caused to the normal cells, hence, minimize the side effects of radiation therapy; and (ii) “radiosensitizers”- to enhance the radiation-induced cell death inflicted to the tumor, and thereby minimize the dose of radiation treatment. In the present article, some of the major findings on traditional medicinal plants and active phytochemicals with promising radioprotective or radiosensitizing efficacy have been briefly summarized in a tabular form (Tables
Plants (family) | Radioprotective/radiosensitizing efficacy of extracts/fractions |
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Extracts protected mice against radiation-induced decline in hemoglobin, total leukocyte, and lymphocytes counts, and the clonogenicity of hemopoietic progenitor cells; decreased lipid peroxidation accompanied by a significant elevation in the GSH concentration in the mouse intestine; elevated the peripheral cell count as well as villus height and crypt number accompanied by a decline in goblet and dead cells; hydroalcoholic leaf extract significantly reduced micro nucleated polychromatic, normo chromatic erythrocytes, and polychromatic/normochromatic erythrocyte ratio in γ-irradiated mice bone marrow cells (Baliga et al., |
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Leaf extract showed radioprotective efficacy (Bakuridze et al., |
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Hydro-alcoholic extract of bark exhibited radioprotective efficacy in γ-irradiated mice (7.5 Gy) through lowering of lipid peroxidation with significant increase in glutathione levels in serum as well as in liver (Gupta et al., |
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Root extract down-regulated hydroxyproline and Tgfb1 and provides protection in mice with radiation-induced pulmonary fibrosis (Han et al., |
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Ethyl acetate fraction of the stem bark reduced radiation-induced chromosome damage in mice through free radical scavenging and reduction of lipid peroxidation activity (Jagetia and Venkatesha, |
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Leaf extracts exhibited radiosensitizing effect by activating pro-apoptotic signals in neuroblastoma xenografts exposed to single (10 Gy) or fractionated (2 Gy/day × 5 day) doses of radiation (Veeraraghavan et al., |
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Methanol extract protected γ-radiation-induced hemopoietic damage through immunomodulation as well as sequential induction of IL-1β, GM-CSF, and IFN-γ (Guruvayoorappan and Kuttan, |
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Whole-plant extract prevented γ-radiation-induced DNA damage in mice bone marrow(Manu et al., |
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Potentially counteracted UV-B-induced damage in human keratinocytes (HaCaT), through NF-κB and AP-1 translocation and procaspase-3 cleavage (Cimino et al., |
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Extract demonstrated significant depletion in lipid peroxidation and elevation in glutathione and catalase levels before γ-irradiation (5 Gy) to mice (Jindal et al., |
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Methanol extract of the aerial part inhibited UV light and nitric oxide-induced DNA damage on plasmid vector pBR322 and human melanoma (M14) cell growth (Rigano et al., |
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Post-treatment of fruit pulp extract inhibited γ-radiation-induced glutathione depletion and ameliorating lipid peroxidation levels in mice (Sisodia et al., |
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Root exhibited anti-inflammatory ability to reduce the mucosal damage caused by radiation (You et al., |
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Protected against γ-radiation-induced hematopoietic damage in bone marrow of mice by significantly decreasing micronucleus formation and increasing erythropoietin level (Samarth, |
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Aqueous ethanolic leaf extract protected against γ-radiation-induced liver damage in mice through inhibition of of NF-κB translocation and lipid peroxidation, with increases in SOD, CAT, GSH, and FRAP (Sinha et al., |
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Prevented UV-B-induced skin damage in hairless mice by inhibiting the expression of matrix metalloproteinase MMP-2, MMP-9, and MMP-13, vascular endothelial growth factor (VEGF), and cyclooxygenase-2 (COX-2) in the skin; histological evaluation showed suppression of Ki-67 and CD31-positive cells expression induced by irradiation (Kimura and Sumiyoshi, |
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Red ginseng showed photoprotective effect of against ultraviolet radiation-induced chronic skin damage in the hairless mouse (Lee et al., |
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Found to protect the clastogenic effects of radiation as seen from decreased number of micronuclei and chromosomal aberrations percentage (Harikumar and Kuttan, |
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Inhibited UV-B-induced hyperplasic response and increased p53-positive cells in hairless mouse epidermis (da Silva et al., |
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Showed protective effects in UV-A and UV-B irradiated human skin fibroblasts (Pacheco-Palencia et al., |
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Extract inhibited γ-radiation (3 Gy) induced lipid peroxidation and elevated glutathione levels in irradiated mice (Jindal et al., |
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Inhibited UV-induced activation of NF-κB and AP-1 in cultured mouse epidermal cells (Huang et al., |
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Extract inhibited γ-radiation-induced DNA damage through scavenging of free radicals in cultured splenocytes of mice (Jagetia et al., |
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Combination treatment of dichloromethane extract with γ-radiation (1–4 Gy) declined viability of HeLa cells by increasing lactate dehydrogenase and decreasing glutathione S-transferase activity (Rao and Rao, |
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Reduced side effects of conventional radiotherapy in cancer (Kienle and Kiene, |
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Combination treatment with Vit.C protected against γ-radiation-induced testicular damage in rats through antioxidant activity (Adaramoye et al., |
Compounds/plants (family) | Radioprotective/radiosensitizing efficacy (reference) |
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Down-regulated γ-ray-induced ICAM-1 expression via inhibition of both AP-1 activation and JNK pathway in human umbilical vein endothelial cells (HUVECs; Son et al., |
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Enhanced cellular toxicity with decreased clonogenic survival in combination with radiation (4 Gy) on redioresistant head and neck squamous carcinoma cell line (Eder-Czembirek et al., |
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Concurrent chemoradiation with capecitabine and weekly irinotecan showed promising efficacy in preoperative treatment for rectal cancer (Phase I and II study; (Klautke et al., |
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Combination regimen with radiation enhanced the efficiency of radiotherapy by increased oxygen diffusion in the brain and elevated the partial brain oxygen level in rat C6 glioma model (Sheehan et al., |
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Protected γ-radiation-induced DNA damage and lipid peroxidation in cultured human lymphocytes (Srinivasan et al., |
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Enhanced radiation-induced cytotoxicity and apoptosis in human breast cancer cell line (MCF-7) through down-regulation of Bcl-2 and COX-2 gene, and up-regulation of p53 and p21 (Kumar et al., |
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Combination treatment with 4 Gy X-ray irradiation enhanced single and double strand DNA break and inhibited DNA repair system in human lung adenocarcinoma cell line (A549), induced apoptosis through up-regulation of p53 and downregulation of Bcl-2 protein (Li et al., |
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Suppressed inflammation and photoageing associated with chronic UV-B exposure by diminishing IL-1β and IL-6 production, and blocked infiltration of macrophages in the integuments of SKH-1 hairless mice (Bae et al., |
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Protected against UV-B-induced apoptosis via oxidative stress and JNK1/c-Jun pathway in retinal pigment epithelium cells (Cao et al., |
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Suppressive effect on UV-B radiation-induced matrix metalloproteinases MMP-2 and -9 expression in mouse skin, mediated via the proteasome pathway (Staniforth et al., |
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Increased radiation sensitivity of GL261 murine glioma model (Newcomb et al., |
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Showed radiosensitization via inhibition of NF-κB, altered cyclin B and/or p21WAF1/Cip1 expression, and G2/M arrest in prostate cancer cells; combination with radiation showed enhanced control on primary tumor growth in orthotopic metastatic mouse model; increased cytotoxicity correlated with inhibition of Bcl-xL and survivin, and upregulation of Bax and PARP cleavage in prostate cancer cell line; (Raffoul et al., |
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Liposomal encapsulation of the honokiol showed radiosensitizing activity (5 Gy) in Lewis lung carcinoma cells (LL/2) through induction of apoptosis and angiogenesis suppression (Hu et al., |
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Synergistic interaction with radiation induce toxicity in DU-145 human prostate cancer cells |
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Enhanced the effect of radiation in |
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Prevented UV-B-induced skin damage in hairless mice by inhibiting the expression of matrix metalloproteinase (MMP)-2, MMP-9, and MMP-13, vascular endothelial growth factor (VEGF), and cyclooxygenase-2 (COX-2) in the skin; histological evaluation showed suppression of Ki-67 and CD31-positive cells expression induced by irradiation (Kimura and Sumiyoshi, |
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Showed radiosensitization effect through apoptosis in human cervical cancer cells (Nair et al., |
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Showed protective effect on UV-A and UV-B-induced damage in HaCaT cells by enhancing SOD, GSH-Px activity, reducing intracellular ROS generation and expression of caspase-3 and 8 proteins (Chen et al., |
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Prevented UV-B-induced skin cancer development by increasing in apoptosis proteins, caspase-3 and -8 levels and tumor suppressor protein, p53 in CD-1, SENCAR, and SKH-1 mice (Arasada et al., |
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Caused decrease in E2F2 and E2F3 accompanied by reduced levels of p53, cyclin-dependent kinases, cyclins, CDC25C, mitogen activated protein kinases, Akt signaling, and subsequent inhibition of cell proliferation on skin, 15 and 25 weeks after UV-B exposure (Gu et al., |
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Reduced UV-B-induced cyclooxygenase-2 expression in mouse epidermal cells by blocking mitogen activated protein kinase (MAPK) activation and reactive oxygen species generation (Yoon et al., |
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Augmented x-ray induced cell death in chicken B lymphocyte (Uma Devi et al., |
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Radiomodifying and anticlastogenic effect on Swiss albino mice (Rao et al., |
In Table
In Table
Here, in Table
Again, prospective radiotherapeutic application of herbal formulations composed of traditional medicinal plants, and marketed as Triphala, Abana, Mentat, Septilin, Chyavanaprasha, Oligonol, HemoHIM, Fuzheng zengxiao formula, etc., have been reported by Sandhya et al. (
Over the years, multi-modal therapy involving more than one anticancer agent applied in combination has been found to be favorable in the management of cancer. The precise efficacy and degree of tumor control exhibited by combination regimen, however, remains variable. Although the reasons for variability remain unclear, discovery of additional novel drugs that synergize with an existing radiation therapy would allow multiple combinations to choose from, thereby increasing the likelihood of clinical success. Recently, Edwards et al. (
Natural products in conjunction with irradiation are likely to exert the protective action through several mechanisms. Scavenging of free radicals generated during radiolysis would be a credible mode of action. Hence, naturally occurring polyphenolic compounds and antioxidant vitamins, primarily retinoids, would be the plausible candidates to offer radio-protection. It is a fact that the chances of developing cancer could be minimized through optimum nutritional supplementation by consuming a variety of fruits and vegetables, some of which have displayed chemopreventive activity by inhibiting tumorigenesis induced by chemical carcinogens and other genotoxic agents (Loo,
However, clinical reports on application of plant extracts with antioxidant property as adjuvants in cancer radiotherapy are still sparse in literature. Apparently, there is an apprehension that the antioxidants would protect not only the normal cells, but also the tumors, from the attack of free radicals generated during the course of treatment with ionizing radiation and anticancer agents. The lack of strong experimental evidences to address this concern resulted in poor enthusiasm from radiation oncologists to recommend their patients to consume such antioxidant products during the course of therapy. However, the pros and cons of this aspect have been critically reviewed, based on
In this context, hydrogen peroxide (H2O2) has been known to play a crucial role in the proliferation of cancer cells. In fact, many human cancers, like melanoma, neuroblastoma, colon carcinoma, and ovarian carcinoma, were found to constitutively generate a high amount of H2O2 (Szatrowski and Nathan,
Another category of phytochemicals showing antitumor activity are those which would enhance the generation of ROS, instead of scavenging the cellular free radicals. Such ROS-generators would apparently sensitize cancer cells endowed with persistent oxidative stress to undergo apoptotic death. We have already discussed about the critical maintenance of constitutively produced ROS, which is probably just below the threshold level required to induce apoptosis in tumors, the basal level being much lower in case of normal cells (Droge,
Further, the phytochemicals could also interact directly with molecular pathways involving kinase networks, like mitogen activated protein kinases (MAPK), phosphatidylinositol-3-kinase (PI-3K), etc., thereby showing the potential to inhibit tumor growth in combination with anticancer drugs and radiation therapy by inducing programmed cell death or apoptosis (Garg et al.,
Again, the higher level of ROS could result in the increase in protein tyrosine kinase (PTK)-mediated phosphorylation of epidermal growth factor receptor (EGF-R; Kamata et al.,
The molecular mechanism of anticancer property of plant-derived polyphenolic compounds, such as EGCG, resveratrol, quercetin, genistein, etc., has been primarily attributable to their ability to scavenge the constitutively expressed endogenous redox modulators (H2O2/OH.). Further studies revealed that EGCG inhibited the phosphorylation of MAPK-enzymes, viz. ERK (extracellular signal regulated kinases), JNK (c-Jun N-terminal kinases), and p38-MAPK (p38 mitogen activated protein kinases), activated by UV-B radiation in human epidermal keratinocytes (Katiyar et al.,
In our laboratory, we are investigating the radiomodulating potential of a diethtylether derivative (D7) of diospyrin, an antitumor quinonoid plant-product, in human breast carcinoma cells (MCF-7). It was observed that D7, in combination with radiation, could increase the apoptosis in tumor cells through down-regulation of the anti-apoptotic Bcl-2 and COX-2 gene expression, and up-regulation of pro-apoptotic genes, like p53 and p21. The higher expression of PUMA (p53 upregulated modulator of apoptosis), a pro-apoptotic protein, was also observed in the combination treatment. Further, the up-regulation of p21 expression in irradiated MCF-7 cells was found to be concomitant with the cell cycle arrest in the G1 phase (Kumar et al.,
Cancer patients need to go through extensive treatment involving chemotherapy, surgical intervention, recurring exposure to gamma-irradiation, or a combination therapy. Some traditionally popular medicinal plants have recently gained attention for their ability to modulate a number of signaling pathways that could initiate and facilitate the proliferation of cancer. In many cases, the potency of these compounds/formulations to sensitize the cancer cells to radiotherapy could be corroborated with the inhibition/activation of the relevant molecular markers. However, the literature citations on supporting clinical trials showing similar observations are quite limited. Nevertheless, a number of reports are available on antioxidants being able to protect against radiation-induced oncogenic transformations in experimental systems. Based on these information it has been presumed that supplementation of vitamins in a good measure, and intake of health promoting plant products in the diet might reduce the harmful side effects of standard therapeutic modalities and enhance their selective toxicity toward malignant cells, leading to an overall improvement in the efficacy of anticancer treatment.
Furthermore, the underlying mechanism of survival and proliferation in some types of cancer would reveal the inherent dependence of these cells on their constitutive oxidative stress. This mechanistic interpretation, in the light of the well-studied role of plant-polyphenolics in scavenging cellular free radical species, might resolve the prevailing dilemma on whether antioxidants would provide the desirable relief, to some extent, to the normal cells in preference to the tumor-bearing ones. Again, this hypothesis would be relevant to the radiosensitizing effect exhibited by a few ROS-generating antitumor agents as well. Thus, it is hoped that future research would add up positively, and would bring more of the aforesaid phytochemicals from “bench to bedside” of the suffering humanity seeking relief from the awful maladies of cancer.
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Banasri Hazra is grateful to the Board of Radiation and Nuclear Sciences, Department of Atomic Energy, Mumbai (Grant No. 2008/37/30/BRNS), and the University Grants Commission, New Delhi, for financial support. Subhalakshmi Ghosh is a Research Associate under this program.