Melatonin as an adjuvant in radiotherapy for radioprotection and radiosensitization.

It is estimated that more than half of cancer patients undergo radiotherapy during the course of their treatment. Despite its beneficial therapeutic effects on tumor cells, exposure to high doses of ionizing radiation (IR) is associated with several side effects. Although improvements in radiotherapy techniques and instruments could reduce these side effects, there are still important concerns for cancer patients. For several years, scientists have been trying to modulate tumor and normal tissue responses to IR, leading to an increase in therapeutic ratio. So far, several types of radioprotectors and radiosensitizers have been investigated in experimental studies. However, high toxicity of chemical sensitizers or possible tumor protection by radioprotectors creates a doubt for their clinical applications. On the other hand, the protective effects of these radioprotectors or sensitizer effects of radiosensitizers may limit some type of cancers. Hence, the development of some radioprotectors without any protective effect on tumor cells or low toxic radiosensitizers can help improve therapeutic ratio with less side effects. Melatonin as a natural body hormone is a potent antioxidant and anti-inflammatory agent that shows some anti-cancer properties. It is able to neutralize different types of free radicals produced by IR or pro-oxidant enzymes which are activated following exposure to IR and plays a key role in the protection of normal tissues. In addition, melatonin has shown the ability to inhibit long-term changes in inflammatory responses at different levels, thereby ameliorating late side effects of radiotherapy. Fortunately, in contrast to classic antioxidants, some in vitro studies have revealed that melatonin has a potent anti-tumor activity when used alongside irradiation. However, the mechanisms of its radiosensitive effect remain to be elucidated. Studies suggested that the activation of pro-apoptosis gene, such as p53, changes in the metabolism of tumor cells, suppression of DNA repair responses as well as changes in biosynthesis of estrogen in breast cancer cells are involved in this process. In this review, we describe the molecular mechanisms for radioprotection and radiosensitizer effects of melatonin. Furthermore, some other proposed mechanisms that may be involved are presented.

Down-regulation of TSGA10, AURKC, OIP5 and AKAP4 genes by Lactobacillus rhamnosus GG and Lactobacillus crispatus SJ-3C-US supernatants in HeLa cell line.

BACKGROUND: Cancer testis antigens (CTAs) are considered cancer bio-markers due to their highly specific expression pattern in human malignancies and near absence from normal somatic tissues. Their specific expression has made them potential targets for early dia-gnosis, assessment of patients prognosis and treatment of cancer in recent years. Lactobacilli are a group of probio-tics with anti-cancer, immunomodulatory and other beneficial features. These bacteria have been shown to alter expression of several cancer-related genes. AIM: We investigated the effect of Lactobacillus rhamnosus GG supernatant (LRS) and Lactobacillus crispatus SJ-3C-US supernatant (LCS) on expression of four CTAs (TSGA10, AURKC, OIP5 and AKAP4) in HeLa cell line after synchronization using MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] assay and quantitative real-time polymerase chain reaction. RESULTS: LRS and LCS inhibited HeLa cell growth after 24 h as demonstrated by MTT assay. Expressions of all CTAs were down-regulated after treatment with both supernatants. CONCLUSION: This study showed the role of Lactobacilli in down-regulation of CTAs genes. Such expression change might be involved in the anticancer effects of these Lactobacilli. The underlying mechanisms of these observations are not clear but epigenetic modulatory mechanisms may participate in this process. Future studies are needed to assess functional roles of Lactobacilli in modulation of other cancer-related genes. Key words: probio-tic - cancer testis antigen - bio-marker - HeLa cell line.

Reduction-oxidation (redox) system in radiation-induced normal tissue injury: molecular mechanisms and implications in radiation therapeutics

Every year, millions of cancer patients undergo radiation therapy for treating and destroying abnormal cell growths within normal cell environmental conditions. Thus, ionizing radiation can have positive therapeutic effects on cancer cells as well as post-detrimental effects on surrounding normal tissues. Previous studies in the past years have proposed that the reduction and oxidation metabolism in cells changes in response to ionizing radiation and has a key role in radiation toxicity to normal tissue. Free radicals generated from ionizing radiation result in upregulation of cyclooxygenases (COXs), nitric oxide synthase (NOSs), lipoxygenases (LOXs) as well as nicotinamide adenine dinucleotide phosphate oxidase (NADPH oxidase), and their effected changes in mitochondrial functions are markedly noticeable. Each of these enzymes is diversely expressed in multiple cells, tissues and organs in a specific manner. Overproduction of reactive oxygen radicals (ROS), reactive hydroxyl radical (ROH) and reactive nitrogen radicals (RNS) in multiple cellular environments in the affected nucleus, cell membranes, cytosol and mitochondria, and other organelles, can specifically affect the sensitive and modifying enzymes of the redox system and repair proteins that play a pivotal role in both early and late effects of radiation. In recent years, ionizing radiation has been known to affect the redox functions and metabolism of NADPH oxidases (NOXs) as well as having destabilizing and detrimental effects on directly and indirectly affected cells, tissues and organs. More noteworthy, chronic free radical production may continue for years, increasing the risk of carcinogenesis and other oxidative stress-driven degenerative diseases as well as pathologies, in addition to late effect complications of organ fibrosis. Hence, knowledge about the mechanisms of chronic oxidative damage and injury in affected cells, tissues and organs following exposure to ionizing radiation may help in the development of treatment and management strategies of complications associated with radiotherapy (RT) or radiation accident victims. Thus, this medically relevant phenomenon may lead to the discovery of potential antioxidants and inhibitors with promising results in targeting and modulating the ROS/NO-sensitive enzymes in irradiated tissues and organ injury systems

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Reduction-oxidation (redox) system in radiation-induced normal tissue injury: molecular mechanisms and implications in radiation therapeutics.

Every year, millions of cancer patients undergo radiation therapy for treating and destroying abnormal cell growths within normal cell environmental conditions. Thus, ionizing radiation can have positive therapeutic effects on cancer cells as well as post-detrimental effects on surrounding normal tissues. Previous studies in the past years have proposed that the reduction and oxidation metabolism in cells changes in response to ionizing radiation and has a key role in radiation toxicity to normal tissue. Free radicals generated from ionizing radiation result in upregulation of cyclooxygenases (COXs), nitric oxide synthase (NOSs), lipoxygenases (LOXs) as well as nicotinamide adenine dinucleotide phosphate oxidase (NADPH oxidase), and their effected changes in mitochondrial functions are markedly noticeable. Each of these enzymes is diversely expressed in multiple cells, tissues and organs in a specific manner. Overproduction of reactive oxygen radicals (ROS), reactive hydroxyl radical (ROH) and reactive nitrogen radicals (RNS) in multiple cellular environments in the affected nucleus, cell membranes, cytosol and mitochondria, and other organelles, can specifically affect the sensitive and modifying enzymes of the redox system and repair proteins that play a pivotal role in both early and late effects of radiation. In recent years, ionizing radiation has been known to affect the redox functions and metabolism of NADPH oxidases (NOXs) as well as having destabilizing and detrimental effects on directly and indirectly affected cells, tissues and organs. More noteworthy, chronic free radical production may continue for years, increasing the risk of carcinogenesis and other oxidative stress-driven degenerative diseases as well as pathologies, in addition to late effect complications of organ fibrosis. Hence, knowledge about the mechanisms of chronic oxidative damage and injury in affected cells, tissues and organs following exposure to ionizing radiation may help in the development of treatment and management strategies of complications associated with radiotherapy (RT) or radiation accident victims. Thus, this medically relevant phenomenon may lead to the discovery of potential antioxidants and inhibitors with promising results in targeting and modulating the ROS/NO-sensitive enzymes in irradiated tissues and organ injury systems.

Isolation and screening of rare Actinobacteria, a new insight for finding natural products with antivascular calcification activity.

AIM: Vascular calcification (VC) is a significant pathological process in some life-threatening diseases. Several pathological mechanisms, including transdifferentiation of vascular smooth muscle cells to osteoblast-like cells and apoptosis are involved in VC. Compounds with an inhibitory effect on these processes are potentially efficient medications. In consideration of the multiple biological activities of Actinobacteria, this research was aimed at finding anti-VC metabolite-producing Actinobacteria. METHODS AND RESULTS: After the isolation and identification of Actinobacteria, the effect of their fermentation broth extracts on the apoptosis rate was measured using various methods, for example, ethidium bromide/acridine orange staining, DNA laddering and diphenylamine assays. The effect of the most effective fermentation broth extract of Actinobacteria (FBEA) on the mRNA expression of runt-related transcription factor 2 (Runx2) and osteopontin (OPN) was examined. Finally, the most effective FBEA was fractionated and the chemical composition of anti-VC fractions was analysed using GC-MS. Various VC inhibition rates were observed in the tested FBEA (20 µg ml-1 ; 17·9-60·15%). The inhibition of DNA fragmentation was 7-48%. The FBE with the greatest anticalcification activity belonged to Kribbella sp. UTMC 267 and, according to 16S rRNA analysis, Kribbella sancticallisti with a similarity of 98·53% is its nearest neighbour. The FBE of Kribbella sp. UTMC 267 reduced Runx2 mRNA expression by 2·95-fold and OPN mRNA expression by 28·57-fold, both of which are considered significant (P < 0·05). Finally, GC-MS analysis showed the existence of potent anti-oxidative and anti-inflammation agents in FBE of Kribbella sp. UTMC 267. CONCLUSIONS: Actinobacterial metabolites can provide a new strategy for treating VC diseases by reducing the expression of osteogenic genes, the apoptosis rate and oxidative stress. SIGNIFICANCE AND IMPACT OF THE STUDY: This study highlights the therapeutic potential of Kribbella sp. metabolites and Actinobacteria as a new natural source for drug discovery programs in the nonantibiotic bioactivity field.

The Anti-apoptotic Mechanism of Metformin Against Apoptosis Induced by Ionizing Radiation in Human Peripheral Blood Mononuclear Cells.

BACKGROUND: In a previous article, we showed that metformin (MET) can reduce ionizing radiation (IR) induced apoptosis in human peripheral blood mononuclear cells. However, the anti-apoptotic mechanism of MET against IR remains unclear. The present study attempts to investigate the mechanism of action of MET in limiting X-ray induced apoptosis in human peripheral blood mononuclear cells. MATERIAL AND METHODS: Mononuclear cells were treated with MET for 2 hours and irradiated with 6 MV X-rays. The gene expression levels of BAX, CASP3 and BCL2 were determined 24 hours post irradiation using real time quantitative polymerase chain reaction (qPCR) technique. Furthermore, the protein levels of BAX, CASP3 and BCL2 were analyzed by Western blotting assay. RESULTS: Radiation exposure increased the expressions of BAX and CASP3 genes, and decreased the expression of BCL2 gene in mononuclear cells. Conversely, an increase in BCL2 gene expression along with a decrease in BAX and CASP3 genes expression was observed in MET plus irradiated mononuclear cells. It was found that radiation increased BAX/BCL2 ratio, while MET pretreatment reduced these ratios. Also, treatment with MET without irradiation did not change the expressions of BAX, CASP3 and BCL2 genes. On the other hand, downregulated expression of BCL2 protein and upregulated expressions of BAX and CASP3 proteins were found in 2 Gy irradiated mononuclear cells, while pretreatment with MET significantly reversed this tendency. CONCLUSION: These results suggest that MET can protect mononuclear cells against apoptosis induced by IR through induction of cellular anti-apoptotic signaling.Key words: ionizing radiation - metformin - apoptosis - genes - proteins - blood cells.

The melatonin immunomodulatory actions in radiotherapy.

Radiotherapy has a key role in cancer treatment in more than half of patients with cancer. The management of severe side effects of this treatment modality is a limiting factor to appropriate treatment. Immune system responses play a pivotal role in many of the early and late side effects of radiation. Moreover, immune cells have a significant role in tumor response to radiotherapy, such as angiogenesis and tumor growth. Melatonin as a potent antioxidant has shown appropriate immune regulatory properties that may ameliorate toxicity induced by radiation in various organs. These effects are mediated through various modulatory effects of melatonin in different levels of tissue reaction to ionizing radiation. The effects on the DNA repair system, antioxidant enzymes, immune cells, cytokines secretion, transcription factors, and protein kinases are most important. Moreover, anti-cancer properties of melatonin may increase the therapeutic ratio of radiotherapy. Clinical applications of this agent for the management of malignancies such as breast cancer have shown promising results. It seems anti-proliferative, anti-angiogenesis, and stimulation or suppression of some immune cell responses are the main anti-tumor effects of melatonin that may help to improve response of the tumor to radiotherapy. In this review, the effects of melatonin on the modulation of immune responses in both normal and tumor tissues will be discussed.

Melatonin as an anti-inflammatory agent in radiotherapy.

Radiotherapy is one of the most relevant treatment options for cancer therapy with or without other treatment modalities including immunotherapy, surgery and chemotherapy. Exposure to heavy doses of ionizing radiation during radiotherapy results in short and long term side effects. It appears that many of these side effects are linked to inflammatory responses during treatment or after prolonged use. Inflammation is mediated by various genes and cytokines related to immune system responses caused by massive cell death following radiotherapy. This phenomenon is more obvious, particularly after exposure to clinical doses of radiotherapy. Inflammation is involved in the amplification of acute responses, genomic instability and also long term pathological changes in normal tissues. Moreover, inflammation attenuates responses of the tumor to radiotherapy through some mechanisms such as angiogenesis. Thus, the management of inflammation is one of the most interesting aims in cancer radiotherapy. Melatonin, known as a natural product in the body, has been of much interest for its anti-inflammatory properties. Some studies have proposed melatonin as a novel anti-inflammation agent. This literature review will concentrate on the anti-inflammatory properties of melatonin that may help the management of different inflammatory signaling pathways in both tumor and normal tissues.