Publications by authors named "Badri N Pandey"

34 Publications

Mechanism of thorium-nitrate and thorium-dioxide induced cytotoxicity in normal human lung epithelial cells (WI26): Role of oxidative stress, HSPs and DNA damage.

Environ Pollut 2021 Mar 23;281:116969. Epub 2021 Mar 23.

Radiation Biology & Health Sciences Division, Bhabha Atomic Research Centre, Trombay, Mumbai, 400 085, India; Homi Bhabha National Institute, Anushakti Nagar, Mumbai, 400 094, India. Electronic address:

Inhalation represents the most prevalent route of exposure with Thorium-232 compounds (Th-nitrate/Th-dioxide)/Th-containing dust in real occupational scenario. The present study investigated the mechanism of Th response in normal human alveolar epithelial cells (WI26), exposed to Th-nitrate or colloidal Th-dioxide (1-100 μg/ml, 24-72 h). Assessment in terms of changes in cell morphology, cell proliferation (cell count), plasma membrane integrity (lactate dehydrogenase leakage) and mitochondrial metabolic activity (MTT reduction) showed that Th-dioxide was quantitatively more deleterious than Th-nitrate to WI26 cells. TEM and immunofluorescence analysis suggested that Th-dioxide followed a clathrin/caveolin-mediated endocytosis, however, membrane perforation/non-endocytosis seemed to be the mode of Th internalization in cells exposed to Th-nitrate. Th-estimation by ICP-MS showed significantly higher uptake of Th in cells treated with Th-dioxide than with Th-nitrate at a given concentration. Both Th-dioxide and nitrate were found to increase the level of reactive oxygen species, which seemed to be responsible for lipid peroxidation, alteration in mitochondrial membrane potential and DNA-damage. Amongst HSPs, the protein levels of HSP70 and HSP90 were affected differentially by Th-nitrate/dioxide. Specific inhibitors of ATM (KU55933) or HSP90 (17AAG) were found to increase the Th- cytotoxicity suggesting prosurvival role of these signaling molecules in rescuing the cells from Th-toxicity.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.envpol.2021.116969DOI Listing
March 2021

Estimation and in-situ detection of thorium in human liver cell culture by arsenazo-III based colorimetric assay.

Biometals 2020 02 2;33(1):75-85. Epub 2020 Jan 2.

Radiation Biology & Health Sciences Division, Bhabha Atomic Research Centre, Trombay, Mumbai, 400 085, India.

To understand the biological effects of Thorium-232 (Th) in human cells and animal models as well as to assess mitigation strategies for its detoxification, there is a need to develop a sensitive, specific, high-throughput and easily-implementable assay for detection and estimation of Th in biological samples. Here, we have optimized arsenazo-III dye based colorimetric assay to detect Th in biological samples. The concentration of arsenazo-III (i.e. 50 µM) was optimized, which can reliably estimate Th in the concentration range of 2.5 to 40 µM. The optimized assay can specifically detect Th without interference from other metal ions (La, Ce, U, Fe, Ca, Cu, Zn and Mn). A significant correlation (R = 0.999) was found between arsenazo-III-based detection of Th and total reflection X-ray fluorescence. The conditions of present assay successfully estimated Th in cell culture medium, cell harvesting (trypsin-EDTA) solution and cell lysate obtained from human liver cell culture. Moreover, for the first time, we detected Th in-situ in adherent liver cells in culture after staining with arsenazo-III. This study confirms that Th can be specifically determined in biological samples using arsenazo-III with the sensitivity, which is relevant to thorium toxicity research.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s10534-019-00231-2DOI Listing
February 2020

Primary and secondary bystander effect and genomic instability in cells exposed to high and low linear energy transfer radiations.

Int J Radiat Biol 2019 12 17;95(12):1648-1658. Epub 2019 Sep 17.

Department of Human Genetics, Sri Ramachandra Institute of Higher Education and Research (Deemed to be University), Chennai, India.

Non-Targeted effects (NTE), such as bystander effect (BE) and genomic instability (GI) challenge central dogma of radiation biology. Moreover, there is a need to understand its universality in different type of cells and radiation quality. To study BE (primary and secondary) and GI Human adult dermal fibroblast (HADF) and peripheral blood lymphocytes (PBL) were exposed to low fluence of Am alpha (α) particle and 6 MV X-ray. The BE was carried out by means of co-culture methodology after exposing the cells to both types of radiation and damage was measured using micronucleus assay (MN) and chromosomal aberration assay (CA) in the p1 cells while the GI was followed up in their progeny. A dose-dependent increase in DNA damages (MN and CA) was observed in directly irradiated and bystander cells. The magnitude of BE was higher (6 fold) in cells co-cultured with the α-irradiated cells than that of with X-irradiated cells. Cross exposure of both cell types confirms that radiation induced BE is cell type dependent. In addition, induced DNA damage persisted for a longer population doubling in α-particle irradiated cells. This work adds evidence to secondary bystander response generated from primary bystander normal cells and its dependence to radiation quality.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/09553002.2019.1665208DOI Listing
December 2019

pH-Labile Magnetic Nanocarriers for Intracellular Drug Delivery to Tumor Cells.

ACS Omega 2019 Jul 5;4(7):11728-11736. Epub 2019 Jul 5.

Chemistry Division, Radiation Biology and Health Sciences Division, and Materials Science Division, Bhabha Atomic Research Centre, Trombay, Mumbai 400085, India.

We report the development of pH-labile ascorbic acid-coated magnetic nanocarriers (AMNCs) for effective delivery of the anticancer drug doxorubicin hydrochloride (DOX) to tumor cells. The uniqueness of this drug delivery system lies in the covalent conjugation of DOX through carbamate and hydrazone bonds, resulting in a slow and sustained drug release profile at different environmental acidities. X-ray diffraction and transmission electron microscopy analyses reveal the formation of crystalline single-phase FeO nanoparticles with an average size of 10 nm. The changes in the interfacial characteristics of the nanocarriers and the presence of organic coatings are probed by infrared spectroscopy, dynamic light scattering, zeta potential, and thermogravimetric measurements. AMNCs show high colloidal stability in aqueous and cell culture media and possess good magnetic field responsivity and protein resistance characteristics. The drug-loaded nanocarriers exhibited sustained pH-triggered release of drug molecules in acidic mediums, substantial cellular internalization, and significant toxicity toward the proliferation of mouse skin fibrosarcoma (WEHI-164), human breast cancer (MCF-7), and human lung cancer (A549) cells. However, it showed significantly lower toxicity in human normal lung (WI26VA) cells. Overall, these results suggest a pH-sensitive drug release of nanoformulations, which showed selective toxicity to tumor than normal cells.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/acsomega.9b01062DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6682152PMC
July 2019

Direct and bystander effects in human blood lymphocytes exposed to Am alpha particles and the relative biological effectiveness using chromosomal aberration and micronucleus assay.

Int J Radiat Biol 2019 06 29;95(6):725-736. Epub 2019 Mar 29.

a Department of Human Genetics , Sri Ramachandra Institute of Higher Education and Research , Chennai , India.

It is important to understand the significance of alpha (α) radiation-induced bystander effects (RIBE) and its relative biological effectiveness (RBE); this is because the phenomenon is not universal and the mechanism is unclear and because the RBE is widely varying and projected to be very high. Isolated lymphocytes from healthy volunteers ( = 10) were exposed to either low fluence α-particles (Am), γ-rays (Co), or X-rays (225 kVp and 6 MV). Co-culture methodology was employed to investigate bystander effects (BEs). Chromosomal aberrations (CA) and micronucleus (MN) formation were used to study the BE and calculated RBE. Lymphocytes directly exposed to the types of radiation used showed a dose-dependent increase in the frequency of CA and MN; dose independent increases in the frequency of these chromosomal damages in co-cultured bystander cells, implies that all three types of radiation-induced a BE. The calculated RBE at the level of 5% induced aberrations varied between 9 and 20. The magnitude of low fluence α-particle induced RIBE is higher than in low LET (linear energy transfer) radiation. The RBE also varies depending upon the endpoints used and adds up to targeted effects. Since the endpoint of CA is considered as an important and early marker of risk prediction, the RIBE and RBE using CA as a marker are relevant for radiation protection purposes.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/09553002.2019.1589018DOI Listing
June 2019

Iron-oxide nanoparticles target intracellular HSP90 to induce tumor radio-sensitization.

Biochim Biophys Acta Gen Subj 2019 05 20;1863(5):857-869. Epub 2019 Feb 20.

Radiation Biology & Health Sciences Division, Bhabha Atomic Research Centre, Mumbai 400085, India; Homi Bhabha National Institute, Anushakti Nagar, Mumbai 400085, India. Electronic address:

Background: Nanoparticle-based therapies have emerged as a promising approach to overcome limitations of conventional chemotherapy. Present study investigates the potential of oleic acid-functionalized iron-oxide nanoparticles (MN-OA) to enhance the radiation response of fibrosarcoma tumor and elucidates its underlying mechanism.

Methods: Various cellular and molecular assays (e.g. MTT, clonogenic, cell cycle analysis, cell death, DNA damage/repair) and tumor growth kinetics were employed to investigate the mechanism of MN-OA induced radio-sensitization.

Results: Mouse (WEHI-164) and human (HT-1080) fibrosarcoma cells treated with MN-OA and gamma-radiation (2 Gy) showed a significant decrease in the cell proliferation. Combination treatment showed significant decrease in clonogenic survival of WEHI-164 cells and was found to induce cell cycle arrest, apoptosis and mitotic catastrophe. The mechanism of radio-sensitization was found to involve binding of MN-OA with HSP90, resulting in down-regulation of its client proteins, involved in cell cycle progression (Cyclin B1 and CDC2) and DNA-double strand break repair (e.g. RAD51 and BRCA1). Consistently, longer persistence of DNA damage in cells treated with MN-OA and radiation was observed in the form of γ-H2AX foci. The efficacy and mechanism of MN-OA-induced radio-sensitization was also validated in an immuno-competent murine fibrosarcoma model.

Conclusion: This study reveals the key role of HSP90 in the mechanism of tumor radio-sensitization by MN-OA.

General Significance: Present work provides a deeper understanding about the mechanism of MN-OA-induced tumor radiosensitization, highlighting the role of HSP90 protein. In addition to diagnostic and magnetic hyperthermia abilities, present remarkable radiosensitizing activity of MN-OA would further excite the clinicians to test its anti-cancer potential.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bbagen.2019.02.010DOI Listing
May 2019

Thorium decorporation efficacy of rationally-selected biocompatible compounds with relevance to human application.

J Hazard Mater 2019 03 13;365:952-961. Epub 2018 Nov 13.

Radiation Biology & Health Sciences Division, Bhabha Atomic Research Centre, Trombay, Mumbai, 400 085, India. Electronic address:

During civil, nuclear or defense activities, internal contamination of actinides in humans and mitigation of their toxic impacts are of serious concern. Considering the health hazards of thorium (Th) internalization, an attempt was made to examine the potential of ten rationally-selected compounds/formulations to decorporate Th ions from physiological systems. The Th-induced hemolysis assay with human erythrocytes revealed good potential of tiron, silibin (SLB), phytic acid (PA) and Liv.52 (L52) for Th decorporation, in comparison to diethylenetriaminepentaacetic acid, an FDA-approved decorporation drug. This was further validated by decorporation experiments with relevant human cell models (erythrocytes and liver cells) and biological fluid (blood) under pre-/post-treatment conditions, using inductively coupled plasma mass spectrometry (ICP-MS) and transmission electron microscopy (TEM). Furthermore, density functional theory-based calculations and extended X-ray absorption fine structure (EXAFS) spectroscopy confirmed the formation of Th complex by these agents. Amongst the chosen biocompatible agents, tiron, SLB, PA and L52 hold promise to enhance Th decorporation for human application.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jhazmat.2018.11.038DOI Listing
March 2019

Receptor tyrosine kinase signaling in cancer radiotherapy and its targeting for tumor radiosensitization.

Int J Radiat Biol 2018 07 19;94(7):628-644. Epub 2018 Jun 19.

a Radiation Signaling and Cancer Biology Section, Radiation Biology and Health Sciences Division , Bhabha Atomic Research Centre , Mumbai , India.

Purpose: One of the most important implications of 'Radiation Biology' research is to improve cancer radiotherapy with minimum side effects. In this regard, combination of chemotherapy with radiation has significantly improved tumor control as well as overall survival in a variety of cancers. However, this has been achieved at the cost of significant normal tissue toxicity, due to the lack of specificity of chemotherapy. Membrane-localized receptor tyrosine kinases (RTKs) have been found to play a driving role in various hallmarks of cancer. Moreover, an early successful clinical trial using RTK-antagonist (cetuximab) to improve tumor radiosensitivity has led to an advancement in this field of research. However, a comprehensive review integrating these findings of various oncogenic RTKs, from basic radiobiology-to-radiotherapy clinical trials, is lacking in literature. Therefore, the present review analyses relevant in-vitro, in-vivo, preclinical/clinical studies and postulates the concept of 'Radiation Biology of RTKs in Cancer'.

Conclusions: The present review elucidates the effect of IR on various oncogenic RTKs and their mechanisms, downstream signaling, intracellular translocations, their role in the repair of radiation-induced DNA damage and post-irradiation survival. Based on the knowledge derived from RTK biology and the analysis of relevant clinical trials, this review attempts to identify radiobiological considerations, which could be implemented in future trials, combining radiotherapy with RTK-antagonist. Additionally, we identify the radiosensitizing potential of recently developed RTK-targeted nanoformulations. This review would probably change the Radiation Oncologist's view for translation of tumor-specific radiosensitization in clinic.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/09553002.2018.1478160DOI Listing
July 2018

Cellular and spectroscopic characterization of cancer stem cell-like cells derived from A549 lung carcinoma.

J Cancer Res Ther 2016 Jul-Sep;12(3):1144-1152

Radiation Biology and Health Sciences Division, Bhabha Atomic Research Centre, Mumbai, Maharashtra, India.

Background: Cancer stem cells (CSCs) are increasingly being realized to play a significant role in the mechanism of chemo-, radio-resistance, and metastasis of cancer. However, studies for spectral markers of CSCs using Fourier transform infrared (FT-IR) and circular dichroism (CD) spectroscopy are limited in the literature.

Materials And Methods: In the present study, CSCs obtained from single cell assay of human lung adenocarcinoma (A549) cells were characterized using CD44+/CD24-/low phenotype expression, Hoechst 33342 dye efflux assay, and expression of stemness genes. Spectral changes in cancer cells and clones enriched with CSCs were studied by FT-IR and CD spectroscopy.

Results: The changes in FT-IR spectra of clones enriched with CSCs showed the difference in the secondary protein structure as compared to nonstem cancer cells. Moreover, A549 clone cells showed higher C-O band of carbohydrates and deoxyribose ring vibrations of Z-form of DNA. These results were further corroborated with CD spectroscopy that showed increased alpha helix proteins and difference in DNA conformation in clones enriched with CSCs. FT-IR studies also showed higher imidazole-metal interactions in clones enriched with CSCs. These results are in agreement with higher activity of one of the metalloproteins that is, superoxide dismutase in clones enriched with CSCs and their increased radioresistance.

Conclusions And General Significance: Overall, these observations provide novel FT-IR and CD spectroscopy signatures in A549 clones enriched with CSCs, which may have implications in the quantifying magnitude of CSCs as prognostic markers in cancer therapy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.4103/0973-1482.171365DOI Listing
March 2017

Differential diagnosis of lung cancer, its metastasis and chronic obstructive pulmonary disease based on serum Vegf, Il-8 and MMP-9.

Sci Rep 2016 11 4;6:36065. Epub 2016 Nov 4.

Radiation Biology and Health Sciences Division, Bhabha Atomic Research Centre, Trombay, Mumbai 400 085, India.

Chronic obstructive pulmonary disease (COPD) patients are at higher risk of developing lung cancer and its metastasis, but no suitable biomarker has been reported for differential diagnosis of these patients. Levels of serum biomarkers (VEGF, IL-8, MMP-9 and MMP-2) were analyzed in these patients, which were compared with healthy donors (HD). Levels of VEGF (P < 0.005) and MMP-9 (P < 0.05) were significantly higher in COPD patients than HD. Compared to HD, a decrease in IL-8 (~8.1 folds; P < 0.0001) but an increase in MMP-9 (~1.6 folds; P < 0.05) levels were observed in the lung cancer patients. Cancer patients showed significantly (P < 0.005) lower levels of serum VEGF (1.9 folds) and IL-8 (~9 folds) than the COPD patients. VEGF level was significantly higher (2.6 folds; P < 0.0005) in metastatic than non-metastatic cancer patients. However, MMP-2 didn't show significant variation in these patients. The Youden's index (YI) values for lung cancer diagnosis in HD using IL-8 was 0.55 with 83.3% overall accuracy. VEGF was able to diagnose COPD in HD with better YI (0.38) and overall accuracy (70.6%). IL-8 was able to diagnose cancer in COPD patients and HD with YI values of 0.35, 0.55 with 71% and 83.3% overall accuracy, respectively.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/srep36065DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5095766PMC
November 2016

Relevance of radiobiological concepts in radionuclide therapy of cancer.

Int J Radiat Biol 2016 26;92(4):173-86. Epub 2016 Feb 26.

b Radiation Biology and Health Sciences Division , Bhabha Atomic Research Centre , Mumbai ;

Purpose: Radionuclide therapy (RNT) is a rapidly growing area of clinical nuclear medicine, wherein radionuclides are employed to deliver cytotoxic dose of radiation to the diseased cells/tissues. During RNT, radionuclides are either directly administered or delivered through biomolecules targeting the diseased site. RNT has been clinically used for diverse range of diseases including cancer, which is the focus of the review.

Conclusions: The major emphasis in RNT has so far been given towards developing peptides/antibodies and other molecules to conjugate a variety of therapeutic radioisotopes for improved targeting/delivery of radiation dose to the tumor cells. Despite that, many of the RNT approaches have not achieved their desired therapeutic success probably due to poor knowledge about complex and dynamic (i) fate of radiolabeled molecules; (ii) radiation dose delivered; (iii) cellular heterogeneity in tumor mass; and (iv) cellular radiobiological response. Based on understanding gathered during recent years, it may be stated that besides the absorbed dose, the net radiobiological response of tumor/normal cells also determines the clinical response of radiotherapeutic modalities including RNT. The radiosensitivity of tumor/normal cells is governed by radiobiological phenomenon such as radiation-induced bystander effect, genomic instability, adaptive response and low dose hyper-radiosensitivity. These concepts have been well investigated in the context of external beam radiotherapy, but their clinical implications during RNT have received meagre attention. In this direction, a few studies performed using in vitro and in vivo models envisage the possibilities of exploiting the radiobiological knowledge for improved therapeutic outcome of RNT.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3109/09553002.2016.1144944DOI Listing
July 2016

The interaction of human serum albumin with selected lanthanide and actinide ions: Binding affinities, protein unfolding and conformational changes.

Biochimie 2016 Apr 25;123:117-29. Epub 2016 Jan 25.

Radiation Biology and Health Sciences Division, Bhabha Atomic Research Centre, Mumbai 85, India.

Human serum albumin (HSA), the most abundant soluble protein in blood plays critical roles in transportation of biomolecules and maintenance of osmotic pressure. In view of increasing applications of lanthanides- and actinides-based materials in nuclear energy, space, industries and medical applications, the risk of exposure with these metal ions is a growing concern for human health. In present study, binding interaction of actinides/lanthanides [thorium: Th(IV), uranium: U(VI), lanthanum: La(III), cerium: Ce(III) and (IV)] with HSA and its structural consequences have been investigated. Ultraviolet-visible, Fourier transform-infrared, Raman, Fluorescence and Circular dichroism spectroscopic techniques were applied to study the site of metal ions interaction, binding affinity determination and the effect of metal ions on protein unfolding and HSA conformation. Results showed that these metal ions interacted with carbonyl (CO..:)/amide(N..-H) groups and induced exposure of aromatic residues of HSA. The fluorescence analysis indicated that the actinide binding altered the microenvironment around Trp214 in the subdomain IIA. Binding affinity of U(VI) to HSA was slightly higher than that of Th(IV). Actinides and Ce(IV) altered the secondary conformation of HSA with a significant decrease of α-helix and an increase of β-sheet, turn and random coil structures, indicating a partial unfolding of HSA. A correlation was observed between metal ion's ability to alter HSA conformation and protein unfolding. Both cationic effects and coordination ability of metal ions seemed to determine the consequences of their interaction with HSA. Present study improves our understanding about the protein interaction of these heavy ions and their impact on its secondary structure. In addition, binding characteristics may have important implications for the development of rational antidote for the medical management of health effects of actinides and lanthanides.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.biochi.2016.01.012DOI Listing
April 2016

The interaction of actinide and lanthanide ions with hemoglobin and its relevance to human and environmental toxicology.

J Hazard Mater 2016 Apr 29;307:281-93. Epub 2015 Dec 29.

Radiation Biology and Health Sciences Division, Bhabha Atomic Research Centre, Mumbai 400 085, India.

Due to increasing use of lanthanides/actinides in nuclear and civil applications, understanding the impact of these metal ions on human health and environment is a growing concern. Hemoglobin (Hb), which occurs in all the kingdom of living organism, is the most abundant protein in human blood. In present study, effect of lanthanides and actinides [thorium: Th(IV), uranium: U(VI), lanthanum: La(III), cerium: Ce(III) and (IV)] on the structure and function of Hb has been investigated. Results showed that these metal ions, except Ce(IV) interacted with carbonyl and amide groups of Hb, which resulted in the loss of its alpha-helix conformation. However, beyond 75μM, these ions affected heme moiety. Metal-heme interaction was found to affect oxygen-binding of Hb, which seems to be governed by their closeness with the charge-to-ionic-radius ratio of iron(III). Consistently, Ce(IV) being closest to iron(III), exhibited a greater effect on heme. Binding constant and binding stoichiometry of Th(IV) were higher than that of U(VI). Experiments using aquatic midge Chironomus (possessing human homologous Hb) and human blood, further validated metal-Hb interaction and associated toxicity. Thus, present study provides a biochemical basis to understand the actinide/lanthanide-induced interference in heme, which may have significant implications for the medical and environmental management of lanthanides/actinides toxicity.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jhazmat.2015.12.029DOI Listing
April 2016

Magnetic nanoparticle-mediated hyperthermia therapy induces tumour growth inhibition by apoptosis and Hsp90/AKT modulation.

Int J Hyperthermia 2015 29;31(8):909-19. Epub 2015 Sep 29.

a Radiation Biology and Health Sciences Division , Bhabha Atomic Research Centre , Trombay , Mumbai , India .

Purpose: We have evaluated the hyperthermia efficacy of oleic acid-functionalised Fe(3)O(4) magnetic nanoparticles (MN-OA) under in vivo conditions and elucidated the underlying mechanism of tumour growth inhibition.

Materials And Methods: The efficacy and mechanism of tumour growth inhibition by MN-OA-mediated magnetic hyperthermia therapy (MHT) was evaluated in a murine fibrosarcoma tumour model (WEHI-164) using techniques such as TUNEL assay, Western blotting (WB), immunofluorescence (IF) staining and histopathological examination. In addition, bio-distribution of MN-OA in tumour/other target organs and its effect on normal organ function were studied by Prussian blue staining and serum biochemical analysis, respectively.

Results: MN-OA-induced MHT resulted in significant inhibition of tumour growth as determined by measurement of tumour volume, as well as by in vivo imaging of tumour derived from luciferase-transfected WEHI-164 cells. Histopathology analysis showed presence of severe apoptosis and reduced tumour cells proliferation, which was further confirmed by TUNEL assay, reduced expression of Ki-67 and enhanced level of cleaved caspase-3, in tumours treated with MHT. Moreover, expression of heat stress marker, Hsp90 and its client protein, AKT/PKB was reduced by ∼50 and 80%, respectively, in tumours treated with MHT as studied by WB and IF staining. Serum analysis suggested insignificant toxicity of MN-OA (in terms of liver and kidney function), which was further correlated with minimal accumulation of MN-OA in target organs.

Conclusions: These results suggest the involvement of apoptosis and Hsp90/AKT modulation in MN-OA-mediated MHT-induced tumour growth inhibition.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3109/02656736.2015.1075072DOI Listing
October 2016

Effect of proton and gamma irradiation on human lung carcinoma cells: Gene expression, cell cycle, cell death, epithelial-mesenchymal transition and cancer-stem cell trait as biological end points.

Mutat Res 2015 Oct 26;780:35-46. Epub 2015 Jul 26.

Radiation Biology and Health Sciences Division, Bhabha Atomic Research Centre, Mumbai 400085, India.

Proton beam therapy is a cutting edge modality over conventional gamma radiotherapy because of its physical dose deposition advantage. However, not much is known about its biological effects vis-a-vis gamma irradiation. Here we investigated the effect of proton- and gamma- irradiation on cell cycle, death, epithelial-mesenchymal transition (EMT) and "stemness" in human non-small cell lung carcinoma cells (A549). Proton beam (3MeV) was two times more cytotoxic than gamma radiation and induced higher and longer cell cycle arrest. At equivalent doses, numbers of genes responsive to proton irradiation were ten times higher than those responsive to gamma irradiation. At equitoxic doses, the proton-irradiated cells had reduced cell adhesion and migration ability as compared to the gamma-irradiated cells. It was also more effective in reducing population of Cancer Stem Cell (CSC) like cells as revealed by aldehyde dehydrogenase activity and surface phenotyping by CD44(+), a CSC marker. These results can have significant implications for proton therapy in the context of suppression of molecular and cellular processes that are fundamental to tumor expansion.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.mrfmmm.2015.07.006DOI Listing
October 2015

Cellular and molecular effects of beta radiation from I-131 on human tumor cells: a comparison with gamma radiation.

Curr Radiopharm 2014 ;7(2):138-43

Isotope Applications and Radiopharmaceuticals Division, Bhabha Atomic Research Centre, Mumbai- 400085, India.

To study the comparative effects of beta radiation emitted from Na(131)I with equivalent dose of (60)Co γ- radiation across a range of tumor types and underlying mechanism of cytotoxicity. Different tumor cell lines of various tissue origin viz. Raji, U937, A431 and MCF-7 were irradiated with beta radiation emitted from Na(131)I and equivalent dose of (60)Co γ- radiation (0.4 Gy). Cellular toxicity and apoptosis study were carried out in four cell lines and the effects were compared. Gene expression studies of P21, RAD51 and BAX genes were analyzed by q-PCR after β- and γ-irradiation. Cell viability (trypan blue assay) and apoptosis (DNA fragmentation and cleavage of PARP assays) studies for both types of radiation showed that among the four cell lines, A431 is most radio-resistant while MCF-7 and U937 are moderately radiation resistant and Raji cells showed maximum radiosensitivity. However, irradiation of cells with beta radiation from I-131 resulted in enhanced toxicity and apoptosis in tumor cells compared to equivalent dose of γ- rays. Gene expression studies in Raji cells showed difference in magnitude and kinetics of RAD51 and P21 expression after β- and γ-irradiation. Our results showed higher efficacy of beta radiation in induction of tumor cell cytotoxicity and apoptosis compared to an equivalent dose of γ-radiation, which may be associated with differential DNA damage and subsequent repair kinetics in tumor cells after these radiations.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2174/1874471007666140716115938DOI Listing
October 2015

Damaging and protective bystander cross-talk between human lung cancer and normal cells after proton microbeam irradiation.

Mutat Res 2014 May-Jun;763-764:39-44. Epub 2014 Mar 28.

Radiation Signalling and Cancer Biology Section, Radiation Biology and Health Sciences Division, Bhabha Atomic Research Centre, Mumbai 400 085, India. Electronic address:

Most of the studies of radiation-induced bystander effects (RIBE) have been focused on understanding the radiobiological changes observed in bystander cells in response to the signals from irradiated cells in a normal cell population with implications to radiation risk assessment. However, reports on RIBE with relevance to cancer radiotherapy especially investigating the bidirectional and criss-cross bystander communications between cancer and normal cells are limited. Hence, in present study employing co-culture approach, we have investigated the bystander cross-talk between lung cancer (A549) and normal (WI38) cells after proton-microbeam irradiation using γ-H2AX foci fluorescence as a measure of DNA double-strand breaks (DSBs). We observed that in A549-A549 co-cultures, irradiated A549 cells exert damaging effects in bystander A549 cells, which were found to be mediated through gap junctional intercellular communication (GJIC). However, in A549-WI38 co-cultures, irradiated A549 did not affect bystander WI38 cells. Rather, bystander WI38 cells induced inverse protective signalling (rescue effect) in irradiated A549 cells, which was independent of GJIC. On the other hand, in response to irradiated WI38 cells neither of the bystander cells (A549 or WI38) showed significant increase in γ-H2AX foci. The observed bystander signalling between tumour and normal cells may have potential implications in therapeutic outcome of cancer radiotherapy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.mrfmmm.2014.03.004DOI Listing
May 2015

Thorium induced cytoproliferative effect in human liver cell HepG2: role of insulin-like growth factor 1 receptor and downstream signaling.

Chem Biol Interact 2014 Mar 22;211:29-35. Epub 2014 Jan 22.

Radiation Biology and Health Sciences Division, Bhabha Atomic Research Centre, Mumbai 400 085, India.

Thorium-232 ((232)Th), a naturally-occurring actinide has gained significant attention due to its immense potential as a nuclear fuel for advanced reactors. Understanding the biological effects of (232)Th would significantly impact its efficient utilization with adequate health protection. Humans administered with (232)Th (thorotrast patients) or experimental animal models showed that liver is one of the major sites of (232)Th accumulation. Present study reports cellular effects of (232)Th-nitrate in a human-derived liver cell (HepG2). Results showed that the low concentration of (232)Th (0.1-10 μM) induced proliferation of HepG2 cells which was inhibited by the pre-treatment of cells with neutralizing antibody against insulin-like growth factor 1 receptor (IGF-1R). Consistently, (232)Th treatment was found to increase the phosphorylated level of IGF-1R-associated molecule, IRS1 which serves to activate PI3K and MAPK signaling pathways. Pre-treatment with specific inhibitors of PI3K (LY294002) or JNK-MAPK (SP600125) significantly abrogated the cytoproliferative effect of (232)Th. Immunofluorescence analysis showed increased levels of phospho-Akt and phospho-JNK, downstream kinases of IGF-1R, in (232)Th-treated HepG2 cells suggesting the role of IGF-1R-mediated signaling in (232)Th-stimulated cell proliferation. The cell cycle analysis showed that (232)Th increased S and G2-M cell fractions concomitant to the increase of cyclin-E level. Thus, the present investigation highlights the role of IGF-1R-mediated signaling in the cytoproliferative effect of (232)Th in human liver cells at low concentration.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.cbi.2014.01.006DOI Listing
March 2014

Endothelial Dll4-Notch signaling in tumor microenvironment: is there any hidden therapeutic opportunity?

Transl Lung Cancer Res 2013 Dec;2(6):439-41

Radiation Signaling and Cancer Biology Section, Radiation Biology and Health Sciences Division, Bhabha Atomic Research Centre, Mumbai-400 085, India.

Tumor microenvironmental cross-talk between endothelial and cancer cells plays an essential role in growth, progression and therapeutic outcome of cancer. In response to tumor cell-derived vascular endothelial growth factor (VEGF), the endothelial delta-like ligand 4 (Dll4) regulates angiogenesis and tumor growth via Notch signaling. However, in view of intriguing effects of emerging Dll4-Notch signaling in various tumor types, the missing links need to be elucidated for development of this signaling as a possible therapeutic target for cancer therapy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3978/j.issn.2218-6751.2013.09.01DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4367634PMC
December 2013

Dosimetry and radiobiological studies of automated alpha-particle irradiator.

J Environ Pathol Toxicol Oncol 2013 ;32(3):263-73

Mechanical Design and Prototype Development Division, Bhabha Atomic Research Centre, Trombay, Mumbai, India.

Understanding the effect of alpha radiation on biological systems is an important component of radiation risk assessment and associated health consequences. However, due to the short path length of alpha radiation in the atmosphere, in vitro radiobiological experiments cannot be performed with accuracy in terms of dose and specified exposure time. The present paper describes the design and dosimetry of an automated alpha-particle irradiator named 'BARC BioAlpha', which is suitable for in vitro radiobiological studies. Compared to alpha irradiators developed in other laboratories, BARC BioAlpha has integrated computer-controlled movement of the alpha-particle source, collimator, and electronic shutter. The diaphragm blades of the electronic shutter can control the area (diameter) of irradiation without any additional shielding, which is suitable for radiobiological bystander studies. To avoid irradiation with incorrect parameters, a software interlock is provided to prevent shutter opening, unless the user-specified speed of the source and collimator are achieved. The dosimetry of the alpha irradiator using CR-39 and silicon surface barrier detectors showed that ~4 MeV energy of the alpha particle reached the cells on the irradiation dish. The alpha irradiation was also demonstrated by the evaluation of DNA double-strand breaks in human cells. In conclusion, 'BARC BioAlpha' provides a user-friendly alpha irradiation system for radiobiological experiments with a novel automation mechanism for better accuracy of dose and exposure time.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1615/jenvironpatholtoxicoloncol.2013009650DOI Listing
January 2014

Differential response of DU145 and PC3 prostate cancer cells to ionizing radiation: role of reactive oxygen species, GSH and Nrf2 in radiosensitivity.

Biochim Biophys Acta 2014 Jan 9;1840(1):485-94. Epub 2013 Oct 9.

Radiation Biology and Health Sciences Division, Bhabha Atomic Research Centre, Mumbai 400 085, India.

Background: Radioresistance is the major impediment in radiotherapy of many cancers including prostate cancer, necessitating the need to understand the factors contributing to radioresistance in tumor cells. In the present study, the role of cellular redox and redox sensitive transcription factor, Nrf2 in the radiosensitivity of prostate cancer cell lines PC3 and DU145, has been investigated.

Materials And Methods: Differential radiosensitivity of PC3 and DU145 cells was assessed using clonogenic assay, flow cytometry, and comet assay. Their redox status was measured using DCFDA and DHR probes. Expression of Nrf2 and its dependent genes was measured by EMSA and real time PCR. Knockdown studies were done using shRNA transfection.

Results: PC3 and DU145 cells differed significantly in their radiosensitivity as observed by clonogenic survival, apoptosis and neutral comet assays. Both basal and inducible levels of ROS were higher in PC3 cells than that of DU145 cells. DU145 cells showed higher level of basal GSH content and GSH/GSSG ratio than that of PC3 cells. Further, significant increase in both basal and induced levels of Nrf2 and its dependent genes was observed in DU145 cells. Knock-down experiments and pharmacological intervention studies revealed the involvement of Nrf2 in differential radio-resistance of these cells.

Conclusion: Cellular redox status and Nrf2 levels play a causal role in radio-resistance of prostate cancer cells.

General Significance: The pivotal role Nrf2 has been shown in the radioresistance of tumor cells and this study will further help in exploiting this factor in radiosensitization of other tumor cell types.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bbagen.2013.10.006DOI Listing
January 2014

Cellular internalization and mechanism of cytotoxicity of ¹³¹I-rituximab in Raji cells.

J Environ Pathol Toxicol Oncol 2013 ;32(2):91-9

Radiopharmaceuticals Division, Bhabha Atomic Research Centre, Mumbai, India.

Rituximab labeled with radioiodine (¹³¹I-rituximab) has a large potential to be employed for targeted therapy of non-Hodgkin's lymphoma. Studies of parameters such as cellular internalization, stability of ¹³¹I-rituximab bound to CD20 receptor of tumor cells, and the mechanism underlying cytotoxicity induced by ¹³¹I-rituximab will be useful for better clinical application. In this article we describe the efficacy of ¹³¹I-rituximab in CD20-expressing Raji cells. Rituximab labeled with ¹³¹I was purified on a PD-10 column and characterized using high-performance liquid chromatography and paper electrophoresis. Raji cells treated with ¹³¹I-rituximab (1.85 MBq for 2 hours) were washed then incubated. The culture medium collected from treated cells showed increased radioactivity over a longer period (>6 hours), probably due to the deiodination/degradation of ¹³¹I-rituximab. The tumor cells treated with ¹³¹I-rituximab showed time-dependent internalization of radioactivity, and at 12 hours the radioactivity was almost equally distributed in the membrane and cytoplasm. At 24 hours ~70% of the radioactivity was internalized. Cellular toxicity after ¹³¹I-rituximab treatment showed a time-dependent increase in toxicity as estimated by lactate dehydrogenase. Tumor cells treated with ¹³¹I-rituximab showed significantly higher toxicity and apoptosis compared with the those treated with the same concentration of unlabeled rituximab. The increased apoptotic death in cells treated with ¹³¹I-rituximab was associated with cleavage of poly ADP ribose polymerase and upregulation of p53 protein. This study provides a deeper understanding about the cellular internalization/stability of ¹³¹I-rituximab bound to the CD20 receptor and its efficacy in killing Raji cells.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1615/jenvironpatholtoxicoloncol.2013006843DOI Listing
December 2013

The potential value of the neutral comet assay and the expression of genes associated with DNA damage in assessing the radiosensitivity of tumor cells.

Mutat Res 2012 Oct 9;748(1-2):52-9. Epub 2012 Jul 9.

Radiation Biology and Health Sciences Division, Bhabha Atomic Research Centre, Mumbai 400 085, India.

The assessment of tumor radiosensitivity would be particularly useful in optimizing the radiation dose during radiotherapy. Therefore, the degree of correlation between radiation-induced DNA damage, as measured by the alkaline and the neutral comet assays, and the clonogenic survival of different human tumor cells was studied. Further, tumor radiosensitivity was compared with the expression of genes associated with the cellular response to radiation damage. Five different human tumor cell lines were chosen and the radiosensitivity of these cells was established by clonogenic assay. Alkaline and neutral comet assays were performed in γ-irradiated cells (2-8Gy; either acute or fractionated). Quantitative PCR was performed to evaluate the expression of DNA damage response genes in control and irradiated cells. The relative radiosensitivity of the cell lines assessed by the extent of DNA damage (neutral comet assay) immediately after irradiation (4Gy or 6Gy) was in agreement with radiosensitivity pattern obtained by the clonogenic assay. The survival fraction of irradiated cells showed a better correlation with the magnitude of DNA damage measured by the neutral comet assay (r=-0.9; P<0.05; 6Gy) than evaluated by alkaline comet assay (r=-0.73; P<0.05; 6Gy). Further, a significant correlation between the clonogenic survival and DNA damage was observed in cells exposed to fractionated doses of radiation. Of 15 genes investigated in the gene expression study, HSP70, KU80 and RAD51 all showed significant positive correlations (r=0.9; P<0.05) with tumor radiosensitivity. Our study clearly demonstrated that the neutral comet assay was better than alkaline comet assay for assessment of radiosensitivities of tumor cells after acute or fractionated doses of irradiation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.mrgentox.2012.06.008DOI Listing
October 2012

Broadcasting in the airways: the fifth anniversary of the Radiation Research Podcast (1).

Radiat Res 2012 Jul 11;178(1):99-100. Epub 2012 Jun 11.

Nuclear Engineer, Washington, DC, USA.

The Radiation Research Podcast was funded just over five years ago by a few Radiation Research Society members. To date, the volunteers running the podcast have produced and published online, open access, over 70 audio interviews. The program includes monthly interviews with authors of articles, award winners, and other recordings at conferences, such as round table discussions. We here present an overview of the podcast, from its creation to its fifth birthday, to explain how it is working, how the featured interviews are scheduled, and what future directions are taken. So, stay tuned!
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1667/rr3033.1DOI Listing
July 2012

Role of the translationally controlled tumor protein in DNA damage sensing and repair.

Proc Natl Acad Sci U S A 2012 Apr 26;109(16):E926-33. Epub 2012 Mar 26.

Departments of Radiology, Pharmacology and Physiology, and Biochemistry and Molecular Biology, New Jersey Medical School Cancer Center, University of Medicine and Dentistry of New Jersey, Newark, NJ 07103.

The translationally controlled tumor protein (TCTP) is essential for survival by mechanisms that as yet are incompletely defined. Here we describe an important role of TCTP in response to DNA damage. Upon exposure of normal human cells to low-dose γ rays, the TCTP protein level was greatly increased, with a significant enrichment in nuclei. TCTP up-regulation occurred in a manner dependent on ataxia-telangiectasia mutated (ATM) kinase and the DNA-dependent protein kinase and was associated with protective effects against DNA damage. In chromatin of irradiated cells, coimmunoprecipitation experiments showed that TCTP forms a complex with ATM and γH2A.X, in agreement with its distinct localization with the foci of the DNA damage-marker proteins γH2A.X, 53BP1, and P-ATM. In cells lacking TCTP, repair of chromosomal damage induced by γ rays was compromised significantly. TCTP also was shown to interact with p53 and the DNA-binding subunits, Ku70 and Ku80, of DNA-dependent protein kinase. TCTP knockdown led to decreased levels of Ku70 and Ku80 in nuclei of irradiated cells and attenuated their DNA-binding activity. It also attenuated the radiation-induced G(1) delay but prolonged the G(2) delay. TCTP therefore may play a critical role in maintaining genomic integrity in response to DNA-damaging agents.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1073/pnas.1106300109DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3341051PMC
April 2012

Diospyrin derivative, an anticancer quinonoid, regulates apoptosis at endoplasmic reticulum as well as mitochondria by modulating cytosolic calcium in human breast carcinoma cells.

Biochem Biophys Res Commun 2012 Jan 23;417(2):903-9. Epub 2011 Dec 23.

Department of Pharmaceutical Technology, Jadavpur University, Kolkata 700032, India.

Diospyrin diethylether (D7), a bisnaphthoquinonoid derivative, exhibited an oxidative stress-dependent apoptosis in several human cancer cells and tumor models. The present study was aimed at evaluation of the increase in cytosolic calcium [Ca(2+)](c) leading to the apoptotic cell death triggered by D7 in MCF7 human breast carcinoma cells. A phosphotidylcholine-specific phospholipase C (PC-PLC) inhibitor, viz. U73122, and an antioxidant, viz. N-acetylcysteine, could significantly prevent the D7-induced rise in [Ca(2+)](c) and PC-PLC activity. Using an endoplasmic reticulum (ER)-Ca(2+) mobilizer (thapsigargin) and an ER-IP3R antagonist (heparin), results revealed ER as a major source of [Ca(2+)](c) which led to the activation of calpain and caspase12, and cleavage of fodrin. These effects including apoptosis were significantly inhibited by the pretreatment of Bapta-AM (a cell permeable Ca(2+)-specific chelator), or calpeptin (a calpain inhibitor). Furthermore, D7-induced [Ca(2+)](c) was found to alter mitochondrial membrane potential and induce cytochrome c release, which was inhibited by either Bapta-AM or ruthenium red (an inhibitor of mitochondrial Ca(2+) uniporter). Thus, these results provided a deeper insight into the D7-induced redox signaling which eventually integrated the calcium-dependent calpain/caspase12 activation and mitochondrial alterations to accentuate the induction of apoptotic cell death.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bbrc.2011.12.072DOI Listing
January 2012

Magnitude of radiation-induced DNA damage in peripheral blood leukocytes and its correlation with aggressiveness of thymic lymphoma in Swiss mice.

Int J Radiat Biol 2011 Nov;87(11):1113-9

Radiation Biology and Health Sciences Division, Bhabha Atomic Research Centre, Mumbai, India.

Purpose: The present study is aimed to investigate the magnitude and kinetics of DNA damage in peripheral blood leukocytes of mice exposed to whole body gamma irradiation (WBI; 3 Gy) and its correlation with aggressiveness of thymic lymphoma (TL).

Materials And Methods: DNA damage was monitored in peripheral blood cells of individual mice by comet assay at different intervals of post-irradiation, which were correlated with weight of TL in respective mice at 120th day. To further study genomic radiosensitivity in TL development, peripheral blood samples collected at the 15th and 90th day of post-irradiation from control and WBI animals were irradiated (0.5 Gy) ex vivo followed by assessment of DNA damage by comet assay.

Results: The maximum DNA damage (tail moment) was observed at 5 min after WBI, which decreased at longer period, and was minimum at the 7th day after WBI. However, residual damage was observed in comparison to control and it persisted up to 90 days of irradiation. Tail moment values observed at an early time (5 min) of post-irradiation was better correlated (correlation coefficient, r = 0.84) with weight of TL than at longer time period (60 days; r = 0.21). Our results showed that in ex vivo irradiated (0.5 Gy) peripheral blood, the magnitude of DNA damage was higher in samples obtained from WBI mice than sham-irradiated controls suggesting enhanced genomic radiosensitivity in WBI mice. Genomic susceptibility to radiation observed in peripheral blood from WBI animals showed better correlation with weight of TL at the 15th day (r = 0.9) post-irradiation period than at the 90th day (r = 0.44).

Conclusion: These results suggest that the magnitude of radiation-induced initial DNA damage in peripheral blood leukocytes and genomic radiosensitivity could be an indicator of TL aggressiveness in mice.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3109/09553002.2011.622032DOI Listing
November 2011

Radiosensitization in human breast carcinoma cells by thymoquinone: role of cell cycle and apoptosis.

Cell Biol Int 2011 Oct;35(10):1025-9

Department of Pharmacology, Bombay College of Pharmacy, Mumbai University, India.

TQ (thymoquinone), the bioactive constituent of black seed (Nigella sativa), has been shown to inhibit the growth of various human cancers both in vitro and in vivo. This study reports the radiosensitizing effect of TQ on human breast carcinoma cells (MCF7 and T47D). TQ in combination with single dose of ionizing radiation (2.5 Gy) was found to exert supra-additive cytotoxic effects on both the carcinomas as measured by cell proliferation and colony-formation assays. Annexin V binding and FACS analysis revealed the role of enhanced apoptosis and cell cycle modulation in the mechanism of TQ-mediated radiosensitization, thus supporting TQ as an adjuvant for preclinical testing in cancer chemo-radiotherapy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1042/CBI20100701DOI Listing
October 2011

In vivo space radiation-induced non-targeted responses: late effects on molecular signaling in mitochondria.

Curr Mol Pharmacol 2011 Jun;4(2):106-14

Department of Biochemistry and Molecular Biology, University of Medicine and Dentistry of New Jersey, New Jersey Medical School Cancer Center, Newark, NJ 07103, USA.

The lack of clear knowledge about space radiation-induced biological effects has been singled out as the most important factor limiting the prediction of radiation risk associated with human space exploration. The expression of space radiation-induced non-targeted effects is thought to impact our understanding of the health risks associated with exposure to low fluences of particulate radiation encountered by astronauts during prolonged space travel. Following a brief review of radiation-induced bystander effects and the growing literature for the involvement of oxidative metabolism in their expression, we show novel data on the induction of in vivo non-targeted effects following exposure to 1100 MeV/nucleon titanium ions. Analyses of proteins by two-dimensional gel electrophoresis in non-targeted liver of cranially-irradiated Sprague Dawley rats revealed that the levels of key proteins involved in mitochondrial fatty acid metabolism are decreased. In contrast, those of proteins involved in various cellular defense mechanisms, including antioxidation, were increased. These data contribute to our understanding of the mechanisms underlying the biological responses to space radiation, and support the involvement of mitochondrial processes in the expression of radiation induced non-targeted effects. Significantly, they reveal the cross-talk between propagated stressful effects and induced adaptive responses. Together, with the accumulating data in the field, our results may help reduce the uncertainty in the assessment of the health risks to astronauts. They further demonstrate that 'network analyses' is an effective tool towards characterizing the signaling pathways that mediate the long-term biological effects of space radiation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3330755PMC
http://dx.doi.org/10.2174/1874467211104020106DOI Listing
June 2011

Radiobiological basis in management of accidental radiation exposure.

Int J Radiat Biol 2010 Aug;86(8):613-35

Radiation Biology and Health Sciences Division, Bhabha Atomic Research Centre, Mumbai, India.

Purpose: With increasing utilisation of nuclear technologies in power production, medical and industrial applications, and in a scenario of nuclear terrorism/war, there is an enhanced likelihood of accidental radiation exposure to occupational workers, patients and public. The consequent health effects of the radiation exposure are resultant of interaction of radiation with biological systems and subsequent radiation injury. The present review discusses the knowledge gained in radiation biology that can be exploited for better treatment and management of radiation accident victims.

Results: In comparison with planned radiation exposure during diagnosis/therapy, the management of accidental radiation exposure is quite complicated due to uncertainties in dose, duration, organs involved and radionuclides internalised, and hence, require multi-faceted approaches. However, the options available for dosimetry, decorporation of radionuclides and therapeutic protocols of patients are limited, which provides substantial scope in these areas of research. Moreover, there is a need to fill the gaps in knowledge of radiation action in different dose ranges and post-irradiation windows, which would help in improving therapeutic approaches. Cytogenetic approaches are 'gold standard' for biodosimetry but with limited applications in mass casualty scenario. State-of-the-art technological advancement and high throughput in metabolomics, proteomics and genomics could be employed successfully in developing better biodosimetry for triage in accidental radiation exposure. Furthermore, identification of targets at organs/organelles level of internalised radionuclides would be helpful to develop effective decorporation strategies. Despite substantial research investigating several agents, which could modify radiation effects, only a few could reach up to practical application due to poor bioavailability or toxicity.

Conclusions: Deeper insight into the mechanisms of radiation injury under accidental radiation conditions would be helpful in achieving better biodosimetry, decorporation strategies and improvement in prevention/post-irradiation management of radiation accident patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3109/09553001003746059DOI Listing
August 2010