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Flavonoids are polyphenolic phytochemicals, which occur naturally in plants and possess both anti-oxidant and pro-oxidant properties. Flavonoids are gaining increasing popularity in the pharmaceutical industry as healthy and cost-effective compounds. Flavonoids show beneficial pharmacological activities in the treatment and prevention of various types of diseases. They are natural and less toxic agents for cancer chemotherapy and radiotherapy via regulation of multiple cell signaling pathways and pro-oxidant effects. In this review, we have summarized the mechanisms of action of selected flavonoids, and their pharmacological implications and potential therapeutic applications in cancer therapy. [ABSTRACT FROM AUTHOR]

Purpose: Radiobiological research continues to focus on finding newer strategies for enhanced killing of tumor cells by ionizing radiation. In recent years, chemotherapeutic drugs have been found to possess the capabilities to sensitize tumor cells without affecting the normal cells. There have been increasing research efforts to identify novel and nontoxic compounds which cause minimal or no harm to normal cells but maximize tumor toxicity response to radiation exposure. Extensive researches on flavonoids that are compounds derived from plants have shown that these have promising abilities as radioprotectors and radiosensitizers. Conclusions: In this review, we examine the role of flavonoids as potential radiosensitizers, review the underlying molecular mechanisms and discuss their potential usefulness in improving cancer radiotherapy. It is emphasized that obtaining a deeper insight into the molecular mechanisms underlying the combined action of flavonoids and ionizing radiation may provide new directions for radiobiological research applicable to the much needed enhanced selective tumor cytotoxicity to treatment agents. [ABSTRACT FROM AUTHOR]

Abstract: The current study was performed to assess the potential of 4,5-dihydroxy 1,3-benzene disulfonic acid di sodium salt (Tiron) and glutathione (GSH) either individually or in combination against aluminum (Al)-induced developmental toxicity in fetuses and sucklings of Wistar rats. Female rats were exposed to aluminum chloride at a dose of 345mg/(kgday) oral from days 0 to 16 of gestation and 0 to 16 of post-partum (P.P.). Tiron and GSH were administered at a dose of 471mg/(kgday) i.p. and 100mg/(kgday) oral, respectively, on days 5, 7, 9, 11, 13, 15 and 17 of gestation and post-partum. Al caused reduction in number of corpora lutea, number of implantation sites, placental and fetal weight and stunted growth. Skeletal malformations were also observed in fetuses. Maternal toxicity was demonstrated by reduction in body weight gain. Induction of oxidative stress was also recorded in the brain of mother as well as in fetuses and sucklings after Al exposure. Significant decrease was recorded in reduced glutathione, glutathione reductase (GR), glutathione peroxidase (GPx), catalase (CAT), superoxide dismutase (SOD), acetyl cholinesterase (AChE) and increase was observed in TBARS and glutathione-S-transferase (GST) in brain of pregnant mothers, fetuses and sucklings. Most of the above parameters responded positively with individual therapy with Tiron, but more pronounced beneficial effects on the above-described parameters were observed when Tiron was administered in combination with GSH. Inductively coupled plasma-atomic emission spectroscopy (ICP-AES) studies also showed significantly high concentration of Al in suckling''s brain and maternal blood, brain, placenta and fetal brain. Treatment with Tiron individually or in combination with glutathione, reduced the accumulation of the Al in almost all the organs studied. It is concluded that chelating agents reduced the Al-induced toxicity and Tiron was more effective in reducing blood Al concentration than glutathione when given individually. [Copyright &y& Elsevier]

Herbal polyphenols have gained increased significance because of the promises they hold in the prevention and treatment of cancer. There exists an enormous opportunity for the screening and valuation of natural dietary compounds in the development of an effective chemopreventive drug and radiosensitizer that may be of practical use for patients undergoing cancer therapy. This study describes the effect of the flavonoid ellagic acid (EA) on gamma-irradiated human breast cancer MCF-7 cellsin vitrowhen administered alone or in combination with radiation. It was interesting to find the radioprotective effect of EA on NIH3T3, which is a normal cell line. Irradiation of breast tumor cells in the presence of EA (10 μM) to doses of 2 and 4-Gy gamma radiation produced a marked synergistic tumor cytotoxicity while it was found to aid recovery from the radiation damage to NIH3T3 cells. When cells were given a combined treatment of EA and radiation, the cell death increased to 21.7% and 20.7% in the 2 and 4-Gy-treated cells respectively, significantly (P< 0.05) reducing the capacity of MCF-7 cells to form colonies. Even at 24 h, 38 foci/cell were observed in samples that were given the combined treatment, suggesting the cells' inability in repairing the damage. Also, increased apoptosis in EA+ 2Gy (50%) and EA+ 4 Gy (62%)-treated cells was observed in the the sub-G1 phase of the cell cycle. A 6.2-fold decrease in the mitochondrial membrane potential was observed in the combined treatment of EA and IR that facilitated the upregulation of pro-apopttotic Bax and downregulation of Bcl-2, pushing the MCF-7 cells to undergo an apoptotic cell death. It is suggested that EA may be a potential drug adjuvant for improving cancer radiotherapy by increasing tumor toxicity and reducing the normal cell damage caused by irradiation. [ABSTRACT FROM PUBLISHER]

Abstract: Background: Failure of treatment of cancer in clinic by radio/chemotherapy is generally attributed to tumor resistance. It is, therefore, important to develop strategies to increase the cytotoxicity of tumor cells by radiation in combination with new tumor selective cytotoxic agents. We describe the role of ellagic acid (EA) and γ radiation on the oxidative stress and subsequent cytotoxicity of tumor cells in vitro as well as in vivo and their sparing effects on normal cells. Methods: Ehrlich ascites carcinoma (EAC)-transplanted Swiss mice were intraperitoneally injected with EA followed by radiation treatment of 2 Gy for 4 alternate days. Hela cells were used for in vitro studies. Reactive oxygen species (ROS) level was measured by spectrofluorimetric method by using 2, 7-dichlorodihydrofluoresceindiacetate (DCHFDA) fluorescent probe. Cytotoxicity was measured by Trypan blue dye exclusion test and mitochondrial potential was measured using Rhodamine 123 as a probe. Antioxidant enzymes were measured by spectrophotometric methods. Results: EA was found to generate ROS in tumor cells, which increased, by an order of magnitude when cells were treated with EA in combination with γ radiation. The decrease in mitochondrial potential and the loss of cell viability were remarkably greater in tumor cells from mice treated with EA and radiation than alone treatment with either of them. Moreover, EA was found to protect against radiation-induced oxidative stress in splenic lymphocytes of tumor-transplanted mice. Measurement of antioxidant enzymes such as superoxide dismutase (SOD), catalase, glutathione peroxidase (GSH-Px) and glutathione reductase (GR) in tumor cells showed decrease after treatment with EA and radiation in vivo. Treatment of tumor bearing mice with EA and radiation showed significant decrease in animal''s body weight suggesting reduced tumor burden. Conclusion: Combined treatment of tumor with EA and radiation enhances oxidative stress and cytotoxicity in tumor cells. EA protects normal cells against radiation damage. This may offer potential therapeutic benefit, which warrants clinical study for application in cancer radiotherapy. [Copyright &y& Elsevier]

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. [ABSTRACT FROM AUTHOR]

Purpose: This study examined the effect of liposomal encapsulation of 99mTc-labeled diethylenetriaminepentaacetic acid (metastable technetium labeled DTPA) on its organ distribution and therapeutic effect of optimized neutral liposomal-DTPA against thorium (232Th)-induced liver toxicity and its accumulation in rat animal model. Materials and methods: 99mTc-DTPA was encapsulated in neutral (dipalmitoylphosphatidylcholine:cholesterol) and positively (dipalmitoylphosphatidylcholine:cholesterol:stearylamine) charged liposomes using thin film hydration method. Comparative efficacy of liposomal and free DTPA (11.2 mg/kg) was examined in terms of its effect on 232Th accumulation and subsequent toxicity in the liver and blood of rat administered with 232Th-nitrate (600 μg/kg). Organ distribution of free or liposomal 99mTc-DTPA was determined by solid scintillation counting and 232Th accumulation by Inductively Coupled Plasma-Atomic Emission Spectroscopy. Results: Neutral liposomes encapsulated with 99mTc-DTPA showed more uptake in liver, spleen and blood than with positively charged liposomal- and free- 99mTc-DTPA. Administration of 232Th-nitrate to rat significantly increased the levels of liver toxicity markers and of oxidative injury, which were found to be restored more significantly by neutral liposomal-DTPA than free-DTPA. The accumulation of 232Th in liver and blood of contaminated mice was found to be decreased more significantly by neutral liposomal-DTPA than by free-DTPA. Conclusions: Decorporation and consequent mitigation of 232Th induced toxicity may be significantly improved by liposomal encapsulation of DTPA, a chelating agent. [ABSTRACT FROM AUTHOR]

Purpose: An ethanolic extract of Nigella sativa L. (EE-NS) was investigated for its antioxidant properties and radioprotective effects against γ-radiation-induced oxidative damage. Materials and methods: The radical scavenging activity of the extract was measured by 2,2-diphenyl-1-picrylhydrazyl (DPPH), deoxyribose degradation and plasmid relaxation assays in a cell-free system. DNA damage studies were performed using a single cell gel electrophoresis (SCGE) assay and micronuclei (MN) formation. Moreover, the alterations in lipid peroxidation and antioxidant enzymes were measured by biochemical methods. Results: EE-NS showed significant free radical scavenging and protection against DNA damage in cell free systems. Ex vivo treatment of mouse splenic lymphocytes with an ethanolic extract of N. sativa 1 h prior to irradiation (2 Gy) showed significant prevention of the formation of lipid-peroxides and intracellular reactive oxygen species (ROS), which correlated with radiation-induced apoptosis. Moreover, radiation-induced DNA damage was significantly prevented in splenocytes pre-treated with EE-NS. Swiss albino mice fed orally with the different doses of EE-NS (0–100 mg/kg bw) for five consecutive days followed by 2 Gy whole body irradiation (WBI) showed significant protection against oxidative injury to spleen and liver as measured by lipid peroxidation and the activity of antioxidant enzymes. These results were correlated with the prevention of DNA damage as measured by bone marrow micronuclei assay. Our results suggest that oral feeding of extract resulted in increased survival in mice exposed to WBI (7.5 Gy). Conclusion: The results obtained from the different experimental systems suggest the radioprotective ability of EE-NS involving prevention of radiation-induced oxidative damage. [ABSTRACT FROM AUTHOR]

Purpose: Thorium (232Th), a heavy metal radionuclide that targets the liver and skeleton, has been shown to accumulate in the central nervous system at low levels. The present study was aimed to investigate neurobehavioural and neurochemical changes in mice treated with 232Th at sub-lethal doses. Materials and methods: Swiss albino mice were administered intraperitoneally with thorium nitrate. The chelation-based therapeutic effect of calcium diethylenetriamine pentaacetate (Ca-DTPA) was tested on the 232Th-treated mice. 232Th localisation was determined in brain regions by the Inductively Coupled Plasma-Atomic Emission Spectroscopy (ICP-AES) method. Achetylcholine esterase (AChE) activity in different brain regions was evaluated to assess the cholinergic function of mice CNS. Oxidative damage was evaluated by assessing the activities of antioxidant enzymes (i.e., superoxide dismutase and catalase) and the level of lipid peroxidation. The neurobehavioural alteration in the treated mice was studied by the shuttle box method. Results: 232Th accumulation found in different brain regions followed the order: Cerebellum (Cbl) > cortex (Ctx) > hippocampus (Hp) > striatum (Str). However, removal of 232Th by Ca-DTPA was significant from brain regions like Cbl, Ctx and Str but not from Hp. A significant increase in lipid peroxidation and acetylcholine esterase (AChE) activity was observed in the treated mice but activities of superoxide dismutase and catalase was found substantially decreased. 232Th treatment impaired the learning and memory-based neurobehaviour of the mice. Furthermore, our data suggest that Ca-DTPA injection in 232Th-treated animals failed to improve the neurobehaviour of the treated mice, perhaps because Ca-DTPA could not decorporate 232Th or mitigate 232Th-mediated neurochemical changes effectively from/in hippocampus, a brain region implicated in learning and memory response. Conclusion: Administration of 232Th in mice caused neurobehavioural alteration and impairment of cholinergic function, which might be the consequence(s) of oxidative stress induction in different brain regions. [ABSTRACT FROM AUTHOR]

Purpose: Thorium (232Th, IV) preferentially accumulates in the liver, femur and spleen, which necessitates evaluation of its toxic effect in these organs. The present study was aimed at evaluation of liver function, oxidative stress and histological alterations in these organs. Materials and methods: Swiss albino mice were administered either with Thorium nitrate (10 mg/kg body weight/day equivalent to 1090 pCi/kg body weight/day) for 30 days (1/40th dose of LD50/30; the dose of thorium required to kill 50% of the test cohort within 30 days) intraperitoneally or with calcium salt of diethylenetriamine pentaacetate (Ca-DTPA, 100 μmole/kg body/weight) intravenously or both. Liver function tests and oxidative damage was assessed. The concentration of Th in the tissues was determined by Inductively Coupled Plasma-Atomic Emission Spectroscopy (ICP-AES) method. Results: Administration of Th prevented the increase in the body and liver weight and altered liver functions. Th treatment to mice showed a decrease in the activities and gene expression of antioxidant enzymes, and increased lipid peroxidation and protein carbonylation. The extent of observed oxidative damage was correlated with accumulation of Th in examined organs and further associated with histological alterations. Furthermore it was found that these effects were significantly lower when the chelating agent, Ca-DTPA, was given 1 h after Th injection. Conclusion: Administration of subtoxic concentration of Th to mice markedly altered the liver functions and induced oxidative stress in the liver, femur and spleen of mice. The results further demonstrated that Ca-DTPA significantly protected mice against the toxic effects of Th. [ABSTRACT FROM AUTHOR]