Radioprotective effects of Histamine H2 Receptor Antagonists on Gamma Rays Induced Human Peripheral Blood Lymphocytes | Chapter 11 | Current Overview on Disease and Health Research Vol. 2

 

The purpose of the current study is to investigate the radioprotective effects of histamine H2 receptor antagonists on gamma rays generated clastogenic effects on human peripheral blood cells in vitro. This is done utilising metaphase chromosome for chromosomal aberration and micronuclei analyses. In the clinic, histamine H2 receptor antagonists are used to treat peptic ulcers. Using in vitro metaphase analysis and micronucleus tests, the effects of famotidine and ranitidine on 60Cobalt gamma-ray induced clastogenic effects were examined. Heparinized whole blood from six healthy subjects was donated, and 3Gy of gamma radiation was then applied. Famotidine and ranitidine on gamma-ray induced chromosomal aberration and Micronuclei in vitro in human cells of six donors are examined in detail in the current experiment to evaluate the radioprotective effects of these drugs. Aqueous solutions of ranitidine (500 g/ml) and famotidine (150 g/ml) were introduced to lymphocyte cultures at 0 and 24 hours after they had been started. For chromosomal aberrations and micronucleus analyses, cultures were taken and processed after 48 and 72 hours, respectively. Cultures treated with Famotidine & Ranitidine separately demonstrated a substantial reduction (p 0.0001) in the frequency of chromosomal aberration at 0h and 24h following 3Gy gamma irradiation. Famotidine caused dicentrics to be inhibited by 60.91 percent and 56.42 percent at 0h and 24h, respectively, whereas ranitidine caused dicentrics to be inhibited by 52.11 percent and 43.54 percent and overall aberrations to be inhibited by 53.06 percent and 46.66 percent at 0h and 24h. Famotidine therapy was used to significantly reduce the frequency of micronuclei following 3Gy of gamma radiation, which resulted in inhibition of 48.83 percent (p 0.0001) at 0hr and 5.02 percent (p 0.016) after 24h. The decrease in the frequency of chromosomal aberrations in lymphocytes treated with ranitidine and famotidine at 0 and 24 hours following gamma radiation (3Gy) suggests that drugs may lessen the clastogenic effects of radiation via radical scavenging mechanism, with famotidine being more effective than the ranitidine - histamine H2 receptor antagonists studied. On exposure to gamma radiation, the histamine H2 receptor antagonists ranitidine and famotidine were found to have radioprotective properties.

Author(s) Details:

Narinder Kumar Sharma,
Radiation Biology and Health Sciences Division, Bio-Sciences Group, Bhabha Atomic Research Centre, Mumbai, India.

Please see the link here: https://stm.bookpi.org/CODHR-V2/article/view/7751

Study on Radiosensitization of Human Leukemic Cells by ATR Kinase Inhibitor (VE-821): Phosphoproteomic Analysis | Chapter 8 | New Ideas Concerning Science and Technology Vol. 9

The DNA damage response (DDR) is a critical mechanism for maintaining genomic stability since it promotes cell-cycle arrest and encourages DNA damage repair, resulting in resistance to a variety of genotoxic insults when activated. Ataxia telangiectasia mutated (ATM), DNA-dependent protein kinase (DNA-PK), and ATM and Rad3-related kinase are the three phosphatidylinositol 3-kinase-related kinases (PIKKs) that control radiation-induced DDR (ATR). As a result, inhibiting PIKKs therapeutically may be a promising technique for increasing radiosensitivity in cancer cells. The aim of this chapter was to uncover the molecular mechanisms underlying PIKKs inhibitors' radiosensitization of leukemic cells. We concentrated on VE-821 (3-amino-6-(4-(methylsulfonyl)phenyl)-N-phenylpyrazine-2-carboxamide), a recently developed specific ATR inhibitor that has been documented to have an important radio- and chemo-sensitizing effect limited to cancer cells (mostly p53-deficient) without affecting normal cells. We compared the effects of VE-821 on leukemic cell proliferation, viability, and cell cycle in sham-irradiated and irradiated cells to the effect of another PIKK inhibitor, KU55933, which targets ATM. MOLT-4 cells were radiosensitized by both inhibitors. In addition, we used SILAC-based quantitative phosphoproteomics to explain the mechanism of VE-821's radiosensitizing effect in human promyelocytic leukemic cells HL-60 in detail (p53-negative). 9834 phosphorylation sites were discovered using hydrophilic interaction liquid chromatography (HILIC)-prefractionation with TiO2-enrichment and nano-liquid chromatography – tandem mass spectrometry (LC-MS/MS) study. Further investigation found 328 phosphoproteins that were differentially regulated (false discovery rate 1 percent ). Proteins whose phosphorylation was up- or down-regulated were mainly found in the nucleus and were involved in all phases of the cell cycle and cell division. The effects of VE-821 combined with IR on the mechanisms of the G1/S transition, the intra-S-checkpoint, the G2/M checkpoint, and the function of mitosis-related kinases were all altered. Furthermore, we discovered that inhibiting ATR had an effect on phosphoproteins involved in DDR, gene expression, and apoptosis. Furthermore, sequence motif analysis showed that the behaviours of kinases involved in these processes had changed significantly. Finally, our phosphoproteomic studies allowed us to provide a detailed explanation of ATR kinase inhibition and its effect on cellular response to IR-induced genotoxic stress. Our findings show that ATR plays multiple roles in the response to DNA damage, and that its inhibitor VE-821 is an effective radiosensitizer for leukemic cells.

Author (s) Details
 
Barbora Šalovská
Department of Radiobiology, Faculty of Military Health Sciences in Hradec Králové, University of Defense in Brno, Hradec Kralove, 500 01, Czech Republic.

Aleš Tichý
Department of Radiobiology, Faculty of Military Health Sciences in Hradec Králové, University of Defense in Brno, Hradec Kralove, 500 01, Czech Republic.

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